| t ||, Vt |. 1 1 , I !

I I , k j ri| I , 1 1 , | t j ri] | I 1 1 | | t || | rt ss
ACalcineurin-Dependent Transcriptional
Pathwayfor Cardiac Hypertrophy
a j j rt t im a It | | a |I a m i||it r ir 1 iti1 a a |s a rt 1 ia ] r t st 1
iI| | t a rI Ia i|a rt t a t | t a r, iI| a m t rIa |iI ra It a j -
j rt a t | ir ] ! 1 X .
J effery D. Molkentin,

J ian-Rong Lu,
Christopher L. Antos, BruceMarkham,

J ames Richardson,

J effrey Robbins,

| t sj iIt I| t 1 itt rst sIim a |i I| a I |t a 1 It t a r1 ia t | j t r- StephenR. Grant,

and Eric N. Olson #

Irt j | , I| t rt is a j rt It Ij it a | Iir a | m t |t t a |a r rt sj t r st | t j a rIm t r I t I M t |t t a |a r | it |t ] a r 1 1 r t t |t ]
t I t a r1 it m t t It s It | j t rIrt j | it si] r a |s I| a I ir tt |tt s | t j a rIm t r I t I | a I| t |t ]
a r ir t rt a st ir t t || sitt a r 1 j rt It ir sr I| t sis, t r | a r t t 1 | t | r itt rsiI t I t t a s t a I| t sIt rr M t 1 it a |
sa rt t m t rit t r] a r ita Iit r , a j -rt ] a |a Iit r t I It Ia | t a r1 ia t | t r It r a I | a ||a s
] t r t s, a r 1 ir 1 a t Iit r t I im m t 1 ia It -t a r| ] t r t s, sa t | a s t 1 1 1 1 a rr 1 ir t s | |t1 .
t -fos a r 1 t -myc rt tit t 1 ir | | it r t I a |. , 1 1 1 , a 1 t - | a ||a s, t t a s I ! I I ! -1 \
s| im a a r 1 | ta m t , 1 1 I . | t t a a st s a r 1 t IIt t Is t I t a r- | | i|1 rt r s 1 t sj iIa | M t 1 it a | | t r It r
1 ia t | j t rIrt j | | a tt | t t r t t It r sitt | 1 t t a m t r It 1 ,
| itisit r t I M t |t t a |a r | a r1 it ta st a |a r | it |t ]
| a I I| t a r 1 t r|ir ] m t |t t a |a r m t t | a r ism s I| a I t t a j |t 1 1 1 1 | a rr t I k tt r a t
| j t rIrt j | it si] r a |s ir iIia It 1 a I I| t t t || m t m | ra r t It | ir t ir r a Ii, 1 | it \ ! I I 1 -1 1 1 1
I| t rt j rt ] ra m m ir ] t I t a r1 it m t t It ] t r t t t j rt ssit r

| a | t ra It r t I | a r1 ia t a r 1 Va st a |a r M t |t t a |a r
rt m a ir j t t r| a r 1 t rsIt t 1 . | |a t i1 a Iit r t I I| t st m t t | a -
| t r t Iit s
r ism s is a t t r Ira | issa t ir t a r1 it ta st a |a r| it |t ] a r 1 i||
| t | a r1 it ta st a |a r | t st a rt | | r sIiIa It
| t t riIit a | It r 1 t si] r ir ] r t sIra It ] it s It r j rt tt r Iit r t r
| K 1 t a |I| t it r t t | t r It r a I | t rI wt rI|
Irt a Im t r I t I t a r1 ia t | j t rIrt j | a r 1 | t a rI Ia i|a rt .
1 ! 1 1 | a m j | t it | |t1 .
K a m t rt a s sIa 1 it s | a tt im j |it a It 1 ir Ira t t ||a |a r | a
I
| t rI wt rI| , t t a s I t 1 I
a s a si] r a | It r t a r1 ia t | j t rIrt j | . | r rt sj t r st It m t -
| a r| t -| a tis
t It sIrt It | t r ir t rt a st 1 |t a 1 s t r t r| ir ] | t a rI j rt j a -
I 1 1 | |m t a I| | t a 1
ra Iit r s, ir Ira t t ||a |a r | a
I
t t r t t r Ira Iit r s ir t rt a st M a r-
k r r k r| t r, M it | i] a r \ 1 !
| a r t I a |. , 1 I , | a sIa m a r It t I a |. , 1 1 , 1 t r ] t t I a |. ,
1 1 ! , t t r sisIt r I iI| a rt |t t I | a
I
ir t t t r1 ir a Iir ]
j | sit |t ] it rt sj t r st s iI| t r | a r t t 1 t a r1 ia t t a Ij a I. k
Summary
ta rit I t I | a m t ra | Ia t It rs, ir t |a 1 ir ] a r ] it It r sir | |
k r ] | | , j | t r |t j | rir t | | , a r 1 t r 1 t I| t |ir - | - ,
Inresponsetonumerouspathologic stimuli, themyo-
| it | ir 1 a t t I| t | j t rIrt j | it rt sj t r st ir t a r1 it m t -
cardiumundergoes a hypertrophic responsecharac-
t It s | a r|ir t r t I a |. , 1 1 1 , a 1 t s| im a a r 1 | ta m t , 1 1 1 ,
terizedbyincreasedmyocardial cell sizeandactivation
a 1 t s| im a t I a |. , 1 1 1 , | t iIt t I a |. , 1 1 \ , a |st s| a rt
offetal cardiac genes.Weshowthatcardiachypertro-
I| t a | i|iI It t |t ta It ir Ira t t ||a |a r | a
I
t t r t t r Ira Iit r s.
phyisinducedbythecalcium-dependentphosphatase
1 j t rIrt j | it sIim a |i rt sa |I ir rt j rt ] ra m m ir ] t I ] t r t
calcineurin, whichdephosphorylatesthetranscription
t t j rt ssit r ir I| t a 1 a |I m t t a r1 ia m , sa t | I| a I ] t r t s
factor NF-AT3, enabling it to translocate to the nu-
t r t t 1 ir ] It Ia | j rt It ir ist It rm s |i| t -m t sir | t a t
cleus. NF-AT3 interacts with the cardiac zinc finger
t | a ir M 1 | a r 1 -s| t |t Ia | a t Iir a rt a j -rt ] a |a It 1 ,
transcriptionfactorGATA4,resultinginsynergisticac-
| t rt a s I| t t t rrt sj t r 1 ir ] a 1 a |I ist It rm s, -M 1 | a r 1
tivationof cardiac transcription. Transgenic micethat
-t a r1 ia t a t Iir , a rt 1 t r -rt ] a |a It 1 . | t r a Iria rt Iit
express activated forms of calcineurin or NF-AT3 in
j t j Ii1 t s, a Iria | r a Iria rt Iit Ia t It r k K | , a r 1 | -Ij t r a Iri-
the heart developcardiac hypertrophy andheart fail-
a rt Iit j t j Ii1 t | K | , | it | 1 t t rt a st | |t t 1 j rt ssa rt |
ure that mimic human heart disease. Pharmacologic
ta st 1 i|a Iit r a r 1 r a Iria rt sis, a rt a |st ra j i1 | a j -rt ] a -
inhibitionof calcineurinactivityblocks hypertrophyin
|a It 1 ir I| t | t a rI ir rt sj t r st It | j t rIrt j | it si] r a |s
vivoandinvitro.Theseresults defineanovel hypertro-
rt tit t 1 ir | t m a rt a r 1 Ya ta | i, 1 1 1 . | t m t t | a -
phic signaling pathway and suggest pharmacologic
r ism s ir tt |tt 1 ir t t t r1 ir a It | rt ] a |a Iir ] I| t st t a r1 ia t
approaches topreventcardiac hypertrophyandheart
] t r t s 1 a rir ] | j t rIrt j | a rt a r | r t r , a |I| t a ] | | ir 1 -
failure.
ir ] siIt s It r st tt ra | Ira r st rij Iit r Ia t It rs, ir t |a 1 ir ] st -
ra m rt sj t r st Ia t It r | | , | | - , k | - , a r 1 j , a rt
Introduction
im j t rIa r I It r a t Iita Iit r t I It Ia | t a r1 ia t ] t r t s ir rt -
sj t r st It | j t rIrt j | a 1 t s| im a a r 1 | ta m t , 1 1 1 ,
| a r1 ia t | j t rIrt j | is a r a 1 a j Iitt rt sj t r st t I I| t | t a rI
a 1 t s| im a t I a |. , 1 1 1 , | a ria t I a |. , 1 1 \ , | a rr s t I a |. ,
It tirIa a || a || It rm s t I t a r1 ia t 1 ist a st , ir t |a 1 ir ] I| t st
1 1 ! , | t ta t it -M i|itt }t tit t I a |. , 1 1 t . M t sI rt t t r I|, I| t
a risir ] Irt m | j t rIt r sit r , m t t | a r it a | |t a 1 , m t t a r1 ia |
t a r1 ia t -rt sIrit It 1 tir t Iir ] t r Ira r st rij Iit r Ia t It r| k k \
ir Ia rt Iit r , t a r1 ia t a rr| I| m ia s , t r 1 t t rir t 1 is t r1 t rs, a r 1
| a s a |st | t t r s| t r It | t rt | a irt 1 It r Ira r st rij Iit r a |
] t r t Iit m a Ia Iit r s ir t a r1 ia t t t r Ira t Ii|t j rt It ir ] t r t s.
a t Iita Iit r t I I| t ] t r t s It r k r ] | | Ij t a rt t t j It r a r 1
w| i|t I| t | j t rIrt j | it rt sj t r st is ir iIia || a t t m j t r -
-M 1 | 1 a rir ] | j t rIrt j | 1 t rti] t I a |. , 1 1 I , 1 a st -
sa It r m t t | a r ism I| a I a a ] m t r Is t a r1 ia t t a Ij a I, sa s-
] a a t I a |. , 1 1 I , rt tit t 1 ir M t || t r Iir a r 1 1 |st r ,
Ia ir t 1 | j t rIrt j | t a r |t a 1 It 1 i|a It 1 t a r1 it m t j a I| ,
1 1 I .
| t a rI Ia i|a rt , a r 1 sa 1 1 t r 1 t a I| . | r I| t | r iIt 1 Ia It s,
k r a m | t r t I ir Ira t t ||a |a r si] r a |ir ] j a I| a s | a tt
| t t r im j |it a It 1 ir Ira r s1 a t Iit r t I | j t rIrt j | it sIim a |i.
| t r t t a m j |t , t t t a j a r t t I I| t t t || sa rIa t t rt t t j It rs t | t m t t rrt sj t r 1 t r t t s| t a |1 | t a 1 1 rt sst 1 .
| t ||
I t
It r k r ] | | , | | , a r 1 | - |t a 1 s It a t Iita Iit r t I j | t sj | t |i-
j a st | , rt sa |Iir ] ir I| t j rt 1 a t Iit r t I 1 ia t |] |t t rt | a r 1
ir t siIt | Irij | t sj | a It , | it | ir Ia rr rt sa |Is ir m t | i|ita -
Iit r t I ir Ira t t ||a |a r | a
I
a r 1 a t Iita Iit r t I j rt It ir | ir a st
| | | | a 1 t s| im a a r 1 | ta m t , 1 1 1 , Ya m a ta | i t I a |. ,
1 1 t , l t a t I a |. , 1 1 t . | t rt is a |st t ti1 t r t t I| a I I| t
| a s a r 1 m iIt ] t r -a t Iita It 1 j rt It ir M k | | ir a st j a I| -
a s a rt Ira r s1 a t t rs t I | j t rIrt j | it si] r a |s | t r| a rr
t I a |. , 1 1 1 , rt tit t 1 ir | t rt t t I a |. , 1 1 t . | t t t It r I It
| it | I| t st si] r a |ir ] j a I| a s a rt t t t r1 ir a It 1 1 a rir ]
t a r1 ia t | j t rIrt j | is a r | r t r . 1 t t tt r, a || t I I| t st
j a I| a s a rt a sst t ia It 1 iI| a r ir t rt a st ir ir Ira t t ||a |a r
| a
I
, t t r sisIt r I iI| a t t r Ira | rt ] a |a It r rt |t t I | a
I
ir t t t r1 ir a Iir ] I| t a t IitiIit s t I m a |Iij |t | j t rIrt j | it
si] r a |ir ] j a I| a s.
| r | a r 1 t t ||s , I| t | a
I
, t a |m t 1 a |ir -1 t j t r 1 t r I j | t s -
j | a Ia st t a |t ir t a rir | a s | t t r s| t r It |ir | ir Ira t t ||a |a r
si] r a |ir ] j a I| a s I| a I rt sa |I ir t |t ta Iit r t I ir Ira t t ||a |a r
| a
I
iI| a t Iita Iit r t I I| t im m a r t rt sj t r st . | a |t ir t a -
rir rt ] a |a It s im m a r t rt sj t r st ] t r t s I| rt a ] | 1 t j | t s-
j | t r|a Iit r t I a Ia m i| t I Ira r st rij Iit r Ia t It rs | r t r a s
K | -k s r a t |t a rIa t It rs t I a t Iita It 1 t t ||s rt tit t 1 ir
| a t t I a |. , 1 1 I . 1 r t t 1 t j | t sj | t r|a It 1 | t a |t ir t a rir ,
K | -k Ira r st rij Iit r Ia t It rs Ira r s|t t a It It I| t r a t |t a s
a r 1 1 irt t I| a t Iita It im m a r t rt sj t r st ] t r t s | |a r a ] a r
t I a |. , 1 1 , | t | t I a |. , 1 1 t a , 1 1 t | . | t im m a r t sa j -
j rt ssa r I 1 ra ] s t t |t sj t rir k | sk a r 1 | | ! 1 t sa j -
j rt ss I| t im m a r t rt sj t r st | ir | i| iIir ] t a |t ir t a rir s
a | i|iI It a t Iita It K | -k Ira r st rij Iit r Ia t It rs | a t I
a |. , 1 1 ! , | t | t I a |. , 1 1 t | .
1 t rt t s| t I| a I I| t m t t a r1 ia m a Ii|itt s a t a |-
t ir t a rir -1 t j t r 1 t r I j a I| a It a t Iita It I| t Ira r st rij -
| i] a rt . | r It ra t Iit r s | t I t t r | k k \ a r 1 K | -k 1 ir I| t t -
1 | ri1 sIt m Iit r Ia t It r K | -k 1 1 a rir ] | j t rIrt j | , sa ] ] t sIir ] a
t t r st rta Iit r ir si] r a |ir ] | t I t t r im m a r t t t ||s a r 1 k t | t m a Iit 1 ia ] ra m s t I | k k \ a r 1 K | -k 1 j rt It ir s. | t j t rIit r
t I | k k \ a st 1 a s | a iI ir I| t I t -| | ri1 ssIt m t r t t m j a sst 1
t a r1 it m t t It s a s a m t t | a r ism It r rt sj t r 1 ir ] It t r ti-
a m ir t a t i1 s 1 1 \ 1 1 a r 1 is s| t r | t r t a I| I| t Ia ||-|t r ] I| j rt It ir .
rt r m t r Ia | sIrt ss. 1 a r rt sa |Is s| t I| a I a t Iita It 1 t a |-
| t j t rIit r t I K | -k 1 rt t t tt rt 1 ir I| t t a sI I t -| | ri1 st rt t r
t ir t a rir is | t I| r t t t ssa r a r 1 sa IIit it r I It ir 1 a t t
sj a r r t 1 a m ir t a t i1 s ! I I 1 1 I . | t | t | | t m t |t ] 1 t m a ir | 1 |
t a r1 ia t | j t rIrt j | ir tiIrt a r 1 ir titt . k t Iita Iit r t I
t t It r 1 s Irt m a m ir t a t i1 s \ 1 \ t 1 \ a r 1 I| t t t r st rtt 1 j | t sj | t r|a -
t a |t ir t a rir rt sa |Is ir 1 t j | t sj | t r|a Iit r t I K | -k 1 a r 1
Iit r 1 t m a ir Irt m \ ! I I ! .
I| t sa | st | a t r I ir 1 a t Iit r t I It Ia | t a r1 ia t ] t r t s tia a | k m ir t a t i1 s ! I I 1 1 I t I K | -k 1 t rt Ia st 1 ir -Ira m t It I| t | k | \
| K k -| ir 1 ir ] 1 t m a ir | | | a r 1 a st 1 a s | a iI ir a I t -| | ri1 a ssa
t t m | ir a It ria | m t t | a r ism ir tt |tir ] iIs 1 irt t I ir It ra t Iit r
ir Ira r sIt t It 1 1 II t t ||s.
iI| | k k \ . ra r s] t r it m it t I| a I t t j rt ss a t Iita It 1
It rm s t I t a |t ir t a rir t r K | -k 1 ir I| t | t a rI 1 t tt |t j
t a r1 ia t | j t rIrt j | I| a I j rt ] rt sst s It 1 i|a It 1 t a r1 it -
It r | k k \ ir I| t | t a rI. | t | k k \ | a iI t t r sisIt 1 t I
m t j a I| , iI| ir It rsIiIia | Ii| rt sis, t t r ] t sIitt | t a rI
a m ir t a t i1 s 1 1 \ 1 1 Ia st 1 ir -Ira m t It I| t t a sI | k | \
Ia i|a rt , a r 1 sa 1 1 t r 1 t a I| . | sk a r 1 | | ! 1 t | |t t | I| t
j rt It ir | i] a rt k . | is rt ] it r t I | k k \ t r t t m j a sst s
m t rj | t |t ] it a r 1 m t |t t a |a r rt sj t r st s t I j rim a r t a r-
I| t I t tir t Iir ] t rs a r 1 m t sI t I I| t t a r| t t | It rm ir a s
1 it m t t It s It k r ] | | a r 1 | | , ir 1 it a Iir ] I| a I t a |t ir t a rir
| a I |a t | s I| t a m ir t -It rm ir a | Ira r st rij Iit r a t Iita Iit r 1 t -
is a t t m j t r t r I t I I| t si] r a |ir ] j a I| a s | t rt | I| t st
m a ir , a r 1 I| t rt It rt 1 t t s r t I a t Iita It Ira r st rij Iit r t r Ia t It rs ir 1 a t t | j t rIrt j | . M t rt t tt r, | sk a 1 m ir isIra -
iIs t r ir t a sI. t rt t r ir ] t I a 1 . ! -1 a m t a st t m | rt Iit r t a r j rt tt r I t a r1 ia t | j t rIrt j | a r 1 a sst t ia It 1
t | K k |i| ra r rt sa |It 1 ir I| t i1 t r IiIit a Iit r t I r a m t rt a s j a I| t |t ] ir t a |t ir t a rir Ira r s] t r it m it t . | t st rt sa |Is
| k k \ -ir It ra t Iir ] Ia t It rs, t r t t I | it | a s K | -k 1 . 1 t Iir t a r t tt | si] r a |ir ] j a I| a I| a I t t a j |t s | j t rIrt -
| t t I| t r | k k \ -ir It ra t Iir ] Ia t It rs i1 t r IiIit 1 ir I| is j | it si] r a |s a I I| t t t || m t m | ra r t It t | a r ] t s ir t a r1 ia t
st rt t r i|| | t 1 t st ri| t 1 t |st | t rt . ] t r t t t j rt ssit r a r 1 sa ] ] t sI t j j t rIa r iIit s It r j | a rm a -
K | -k 1 is a m t m | t r t I a m a |Ii] t r t Ia m i| t t r Ia ir ir ] t t |t ] it ir It rtt r Iit r ir It t a r1 ia t | j t rIrt j | a r 1 | t a rI
It a r m t m | t rs, K | -k t , K | -k j , K | -k 1 , a r 1 K | -k \ Ia i|a rt .
M t | a IIrt t I a |. , 1 1 1 , K t rI| rt j t I a |. , 1 1 \ , 1 t t I a |. ,
1 1 ! , 1 t t t I a |. , 1 1 ! , M a sa 1 a t I a |. , 1 1 ! , | a r| t I a |. , Results
1 1 t . | t st Ia t It rs | ir 1 I| t t t r st r sa s | K k st | a t r t t
| | k k k k a s m t r t m t rs t r 1 im t rs I| rt a ] | a | t | | t m t |- Interaction between NF-AT3and GATA4
t ] 1 t m a ir | 1 | | t t r t t I a |. , 1 1 \ , 1 t t t I a |. , 1 a r ir iIia | ir It rt sI a s It i1 t r IiI j rt It ir s, a sir ] I| t
t a sI I t -| | ri1 ssIt m , I| a I m i] | I a t I a s t t Ia t It rs 1 1 ! . | rt t t I I| t NF-AT ] t r t s a rt rt sIrit It 1 ir I| t ir
| t ] a |a Iit r t I | a r1 ia t 1 j t rIrt j | | | a |t ir t a rir
I I
| i] a rt I . | t im m a r t j rt t ij iIa Iit r t I | k k \ a r 1 K | -k 1
k K | -k 1 iI| a | |a ] t j iIt j t Ia ] a r 1 | k k \ , a s ir 1 it a It 1 , t rt Ira r s|a It 1 ir a ra | | iI rt Iit a |t t It |sa It ir I| t j rt st r t t t I
1 !
-m t I| it r ir t .
k r Ii-| |a ] a r Ii| t 1 a s I| t r a st 1 It r t t im m a r t j rt t ij iIa Iit r a ssa s. | rt It ir s t rt rt st |tt 1 | | -| k | | . | a r t s a r 1 I s| t I| t ir tiIrt
Ira r s|a Iit r j rt 1 a t Is. | a r t s 1 ! s| t I| t t t im m a r t j rt t ij iIa Iit r s. | t a r Ii-| |a ] a r Ii| t 1 st |t t Iitt | im m a r t j rt t ij iIa It s K | -k 1 |a r t 1 | a I
1 t t s r t I rt t t ] r itt | k k \ |a r t \ . 1 t t tt r, | t r K | -k 1 is m it t 1 iI| | k k \ , | k k \ is t t im m a r t j rt t ij iIa It 1 a sIt ris| ir |a r t ! .
| | t 1 t m a ir t I | k k \ I| a I ir It ra t Is iI| K | -k 1 a s m a j j t 1 | Ira r s|a Iir ] K | -k 1 -| |a ] iI| a st rit s t I | k k \ 1 t |t Iit r m a Ia r Is s| t r
ir | , It ||t t 1 | t t im m a r t j rt t ij iIa Iit r . | tt r -r a m | t rt 1 |a r t s s| t I| t | k k \ t r | k k t |a r t \ 1 t |t Iit r m a Ia r Is |t a 1 t 1 1 irt t I| t r
I| t ] t |. | t t I| t r |a r t s t t r Ia ir I| t ir 1 it a It 1 | k k \ t r | k k t |a r t ! 1 t |t Iit r m a Ia r Is j |a s K | -k 1 a r 1 t rt im m a r t j rt t ij iIa It 1 iI|
a r Ii-| |a ] a r Ii| t 1 . k || | k k \ 1 t |t Iit r m a Ia r Is t t t t j I 1 \ \ I1 I t ! I 1 \ , | it | |a t | s I| t st t t r 1 tir t Iir ] t r, t rt t t im m a r t j rt t ij iIa It 1 . k
| k k t 1 t |t Iit r m a Ia r I t t r Ia ir ir ] I| t I t tir t Iir ] t rs a s a |st t t im m a r t j rt t ij iIa It 1 iI| K | -k 1 .
| a m m a r t I t t im m a r t j rt t ij iIa Iit r rt sa |Is. | a r 1 | I 1 t r t It I| t I t tir t Iir ] t rs a r 1 K | 1 t si] r a It s I| t r a t |t a r |t t a |ita Iit r si] r a |.
| | t | -It rm ir a | rt ] it r t I K | -k 1 , t r t t m j a ssir ] I| t | t | | t m t |t ] 1 t m a ir | 1 | , a s Ira r s|a It 1 st j a ra It | t r It ] t I| t r iI| | k k \
1 t |t Iit r m a Ia r I 1 1 I , a s ir 1 it a It 1 . | a r t s a r 1 I s| t I| t ir 1 iti1 a a | ir tiIrt Ira r s|a Iit r j rt 1 a t Is |t a 1 t 1 1 irt t I| t r I| t ] t |. | a r t s 1 !
s| t I| t rt sa |Is t I im m a r t j rt t ij iIa Iit r iI| a r Ii-K | k a r Ii| t 1 I| a I rt t t ] r itt s I| t K | -k 1 | 1 | . | is rt ] it r is sa IIit it r I It r ir It ra t Iit r
iI| | k k \ ir 1 it a It 1 | a r a sIt ris| ir |a r t ! .
t t j rt ssit r It t t ||s a r 1 s| t |t Ia | m a st |t , | t rt a s NF- k . | t rt ] it r t I K | -k 1 rt t t tt rt 1 Irt m I| t t a sI I t -
| | ri1 st rt t r t t It r 1 t 1 Irt m a m ir t a t i1 ! I I , | it | is AT3 is t t j rt sst 1 ir a ta rit I t I Iissa t s ir t |a 1 ir ] I| t
| t a rI 1 t t t I a |. , 1 1 ! . r t a r I| t m i1 1 |t t I I| t | t | | t m t |t ] 1 t m a ir , It I| t
t a r| t t | It rm ir a s. | itt r I| t a | i|iI t I K | -k Ia t It rs It m t 1 ia It t | a r ] t s
ir ] t r t t t j rt ssit r ir rt sj t r st It | a
I
si] r a |ir ] ir | t sj t t iIit iI t I ir It ra t Iit r | t I t t r | k k \ a r 1 K | -
k 1 a s It sIt 1 | rt Ira r sIt rm ir ] t a sI iI| I| t rt st a t 1 t t ||s, t t rt t sj t t ia || ir It rt sIt 1 ir I| t Iir 1 ir ] I| a I
| k k \ , a | r t r t IIt t It r t I t a r1 ia t ] t r t t t j rt ssit r , K | -k 1 -| k | \ a t Iita Iit r 1 t m a ir j |a sm i1 a r 1 ta rit a s
| k | \ | K k -| ir 1 ir ] 1 t m a ir | a iI j |a sm i1 s. | r I| is a ssa , a r 1 K | -k 1 t rt a | |t It ir It ra t I. | is ir It ra t Iit r sa ] -
] t sIt 1 a j t It r Iia | m t t | a r ism It r t t a j |ir ] | a
I
si] r a |- K | -k 1 a s a |st It a r 1 It ir It ra t I iI| rt si1 a t s 1 1 I t !
t I | k k ! , | it | t r t t m j a ss t r | I| t tir t Iir ] t r | K k - ir ] It t a r1 ia t Ira r st rij Iit r , a s is | r t r It t t t a r 1 a rir ]
t a r1 ia t | j t rIrt j | . | ir 1 ir ] 1 t m a ir . 1 t t tt r, K | -k 1 1 i1 r t I ir It ra t I iI|
I| t | a sit | t |it -|t t j -| t |it j rt It ir | I t r iI| I| t | k | \ K | -k 1 is a 1 1 I -a m ir t a t i1 j rt It ir iI| a rt ] a |a It r
1 t m a ir a I iIs a m ir t It rm ir a s I| a I m t 1 ia It s r a t |t a r | K k -| ir 1 ir ] 1 t m a ir a |t r t 1 a Ia r t I s| t r .
t ta |i1 a It Ia rI| t r I| t ir It ra t Iit r | t I t t r | k k \ Ira r s|t t a Iit r a r 1 I| t | t | | t m t |t ] 1 t m a ir r t a r iIs
t a r| t t | It rm ir a s I| a I m t 1 ia It s | K k | ir 1 ir ] | i] a rt a r 1 K | -k 1 , I| t rt st a t 1 NF-AT3 t | K k Ira ] m t r I a s
| t ||
I
| i] a rt 1 . | t ] a |a Iit r t I I| t BNP | rt m t It r | K | -k 1 ir | rim a r | a r1 it m t t It s
k | rim a r ra I t a r1 it m t t It s t rt Ira r sit r I| Ira r sIt t It 1 iI| a CAT rt j t rIt r ] t r t |ir | t 1 It I| t BNP ! -I|a r | ir ] rt ] it r a r 1 t t j rt ssit r
tt t It rs t r t t 1 ir ] K | -k 1 , a t Iita It 1 t a |t ir t a rir , t r | k k \ , a s ir 1 it a It 1 . | t rI-t i] | I | t a rs |a It r, t t ||s t rt | a rtt sIt 1 a r 1 | k a t IitiI a s
1 t It rm ir t 1 . | r I| t |a r t |a | t |t 1 1 I I siIt m a Ia r I, a BNP-CAT rt j t rIt r ] t r t , ir | it | I| t K | -k 1 siIt a I 1 I I a s m a Ia It 1 , a s a st 1 .
|
1 I
| -|a | t |t 1 t |i] t r a t |t t Ii1 t j rt | t s t t rrt sj t r 1 ir ] It I| t j t It r Iia | K | -k | ir 1 ir ] siIt s Irt m I| t IL-2 j rt m t It r a r 1 Irt m 1 I I , 1 I I , a r 1
I I | j ! t I I| t BNP ] t r t t rt a st 1 ir ] t | m t | i|iI s| iII a ssa s iI| a r j rt ] ra m m t 1 rt Iit a |t t It |sa It |a r t s \ t r ir tiIrt Ira r s|a It 1 K | -
k 1 |a r t s ! . 1 r | I| t | | -I a r 1 | K | -1 I I j rt | t s it |1 t 1 a sj t t iIit | K k j rt It ir t t m j |t t .
| k
1 I
| -|a | t |t 1 t |i] t r a t |t t Ii1 t j rt | t t t rrt sj t r 1 ir ] It I| t 1 I I BNP siIt a s a st 1 ir ] t | m t | i|iI s| iII a ssa s iI| j rt It ir t t Ira t Is Irt m
r t t r a Ia | ra I t a r1 it m t t It s. M a |Iij |t sj t t iIit t t m j |t t t s t rt ] t r t ra It 1 |a r t , | it | t rt t t m j t It 1 | a r |a | t |t 1 t t ] r a It siIt |a r t I ,
| a I r t I | a r a r rt |a It 1 | -| t t t |i] t r a t |t t Ii1 t |a r t 1 . k 1 1 iIit r t I K | -k 1 a r Ii| t 1 t |im ir a It 1 I| t m a }t r | K k j rt It ir t t m j |t t a r 1 t rt a It 1
a m ir t r It rr a r t t m j |t t a sIt ris| ir |a r t ! , | t rt a s r t r im m a r t ra | | iI st ra m | a 1 r t t IIt t I |a r t \ . | rt t j rt | t a s t |t t Irt j | t rt st 1 t II I| t
| t IIt m t I I| t ] t | ir | t I| t t j t rim t r Is.
Ia st 1 It I| t | k | \ | K k -| ir 1 ir ] 1 t m a ir a r 1 It sIt 1 It r I| t I t tir t Iir ] t rs a r 1 K | , ir It ra t It 1 iI| K | -k 1
a s t IIit it r I| a s Ia ||-|t r ] I| | k k \ | i] a rt I | , |a r t . iIs a | i|iI It ir It ra t I iI| Ia ||-|t r ] I| | k k \ ir Ira r s-
It t It 1 m a m m a |ia r t t ||s. k s a rt j t rIt r j |a sm i1 , t a st 1 | t si1 a t s I 1 1 \ \ t I | k k \ , | it | t t It r 1 Irt m I| t
st t t r 1 tir t Iir ] t r It I| t | It rm ir a s, a |st ir It ra t It 1 iI| j | ! | | | k , | it | t t r Ia ir s Iitt Ia r 1 t m | k | \ | K k -
| ir 1 ir ] siIt s a j sIrt a m t I I| t m ir im a | E1b j rt m t It r K | -k 1 |a r t I , | t rt a s a r ir It rr a | 1 t |t Iit r m a Ia r I
|a t | ir ] I| t st t t r 1 tir t Iir ] t r 1 \ \ I1 I t ! I 1 \ 1 i1 |ir | t 1 It | k . | is rt j t rIt r a s r t I si] r iIit a r I| a t Ii-
ta It 1 | t iI| t r | k | \ -K | -k 1 t r | k k \ a |t r t | a I a s r t I |a r t 1 . | t st t t j t rim t r Is 1 t m t r sIra It 1 I| a I I| t
st t t r 1 tir t Iir ] t r t I | k k \ a s t sst r Iia | It r ir It ra t - sIrt r ] | a t Iita It 1 | I| t I t Ia t It rs It ] t I| t r ir 1 II
Ii| rt | |a sIs | i] a rt | , a s t || a s ir j rim a r r t t r a Ia | Iit r iI| K | -k 1 , | t rt a s I| t K It rm ir a s, I| t IirsI tir t
Iir ] t r, a r 1 I| t | It rm ir a s t rt a r im j t rIa r I It r I| is ra I t a r1 it m t t It s 1 a Ia r t I s| t r . | a ||-|t r ] I| K | -
k 1 a |st ir It ra t It 1 iI| I| t | k | \ -| k k \ | a iI ir I| t ir It ra t Iit r | i] a rt I | . k |st t I r t It , I| t tir t Iir ] t r rt -
] it r a m ir t a t i1 s 1 1 1 ! 1 t I | k k t a s im m a r t j rt - m a m m a |ia r Ira r sIt t Iit r a ssa 1 a Ia r t I s| t r .
t ij iIa It 1 iI| K | -k 1 |a r t ! .
wt a |st It sIt 1 a 1 t |t Iit r m a Ia r I t I K | -k 1 I| a I Mapping the ProteinDeterminants
of GATA4-NF-AT3Interaction t r t t m j a sst 1 t r | I| t | t | | t m t |t ] 1 t m a ir , rt si1 a t s
\ 1 \ t 1 \ . | is rt ] it r a s sa IIit it r I It ir It ra t I iI| t 1 t Iir t Ia rI| t r I| t ir It ra t Iit r | t I t t r | k k \ a r 1
K | -k 1 , t It sIt 1 | t I| t r ir It ra t Iit r s | t I t t r I| t | k k \ | i] a rt I | , |a r t ! . t ] t I| t r, I| t st rt sa |Is ir 1 i-
t a It 1 I| a I I| t | t | | t m t |t ] rt ] it r t I K | -k 1 t t r Ia ir t 1 t t rrt sj t r 1 ir ]
1 !
-m t I| it r ir t -|a | t |t 1 ir tiIrt Ira r s|a -
Iit r j rt 1 a t Is t t a |1 | t 1 t It t It 1 . | t Ira r s|a Iit r t I Ia ||- 1 t It rm ir a r Is I| a I m t 1 ia It ir It ra t Iit r iI| I| t st t t r 1
tir t Iir ] t r t I | k k \ . |t r ] I| | k k \ iI| I| t K | -k 1 1 t |t Iit r m a Ia r I t t r -
Ia ir ir ] rt si1 a t s ! I I 1 1 I Ia st 1 It a | |a ] t j iIt j t a I I| t
| It rm ir a s, It ||t t 1 | im m a r t j rt t ij iIa Iit r iI| a r Ii- Synergistic Activation of the BNP Gene
byGATA4 andNF-AT3 | |a ] a r Ii| t 1 a r 1 | -| k | | , s| t t 1 I| a I I| t I t j rt -
It ir s t t im m a r t j rt t ij iIa It 1 | i] a rt I k , |a r t ! . | t a r Ii- t | t ] ir It ir tt sIi] a It | t I| t r I| t | k k \ -K | -k 1 ir -
It ra t Iit r | a 1 a Ia r t Iit r a | rt |t ir t a r1 ia t ] t r t t t j rt s- | |a ] a r Ii| t 1 1 i1 r t I im m a r t j rt t ij iIa It | k k \ ir I| t
a | st r t t t I K | -k 1 -| |a ] |a r t \ . sit r , t It sIt 1 I| t ANF, BNP, a r 1 cardiac troponin I
j rt m t It rs, | it | a rt a j -rt ] a |a It 1 1 a rir ] | j t rIrt j | , t m a j I| t 1 t It rm ir a r Is t I I| is ir It ra t Iit r m t rt j rt -
t ist |, t It sIt 1 a st rit s t I | k k \ 1 t |t Iit r m a Ia r Is It r I| t ir rt sj t r sitt r t ss It I| t st Ia t It rs ir Ira r sIt t It 1
r t t r a Ia | ra I t a r1 it m t t It s. | t BNP j rt m t It r s| t t 1 It r I| t a | i|iI It | t t t im m a r t j rt t ij iIa It 1 iI| K | -k 1 -
| |a ] . | t si1 a t s 1 I t I | k k \ , | it | t r t t m j a ss a 1 ra m a Iit rt sj t r st a r 1 a s I| t rt It rt a r a |tt 1 Ia rI| t r.
| t ] a |a Iit r t I | a r1 ia t 1 j t rIrt j | | | a |t ir t a rir
I 1
| i] a rt \ . | r | i| iIit r t I k r ] | | - a r 1 | | -| t j t r -
1 t r I 1 j t rIrt j | t I | rim a r | a r1 it t It s |
| sk a r 1 | | ! 1 t
k | | rim a r ra I t a r1 it t It s ir st ra m -Irt t
m t 1 ia m t rt sIim a |a It 1 iI| k r ] | | 1 r M
t r | | 1 M It r I I | r. | t ||s t rt I| t r Iit t 1
a r 1 sIa ir t 1 iI| a r Ii--a t Iir ir a r Ii| t 1 It
rt tt a | sa rt t m t rt s a r 1 1 t t t | sI sIa ir It rt -
tt a | r a t |t i. | sk ! 1 1 r ] Im | a s a 1 1 t 1 It t r t
st I t I t a |Ia rt s a I I| t Iim t t I k r ] | | a 1 1 iIit r .
| t Ia | | K k a s ist |a It 1 Irt m j rim a r
t a r1 it t It t a |Ia rt s Irt a It 1 iI| k r ] | | ir I| t
j rt st r t t t r a | st r t t t I | sk a s ir k a r 1
a r a |tt 1 It r t t j rt ssit r t I GAPDH a r 1 ANF
Ira r st rij Is | 1 t I | |t I.
1 | rim a r ra I t a r1 it m t t It s t rt Ira r -
sit r I| Ira r sIt t It 1 iI| a r K | -k -1 t j t r 1 t r I
luciferase rt j t rIt r ] t r t . | t ||s t rt I| t r
Irt a It 1 iI| k r ] | | t r | | ir I| t j rt st r t t t r
a | st r t t t I | sk , a s 1 t st ri| t 1 a | t tt . | t rI-
t i] | I | t a rs |a It r, t t ||s t rt | a rtt sIt 1 a r 1
|a t iIt ra st a t IitiI a s 1 t It rm ir t 1 .
| t r I| t st t t j t rim t r Is, t a |st a st 1 a t | K k t t j rt ssit r t |i] t r a t |t t Ii1 t j rt | t s t t rrt sj t r 1 ir ] It I| t st st -
| a t r t t s, t a st 1 ] t | m t | i|iI s| iII a ssa s It It sI It r j |a sm i1 t r t t 1 ir ] a t t r sIiIa Iitt | a t Iitt It rm t I I| t
t a |t ir t a rir t a Ia |Iit k sa | a r iI |a t | ir ] I| t | -It rm ir a | | ir 1 ir ] It ir tiIrt Ira r s|a It 1 K | -k 1 j rt It ir ] t r t ra It 1
ir a ra | | iI rt Iit a |t t It |sa It . | t j a Ia Iitt siIt a I 1 I I a a It ir | i| iIt r 1 t m a ir 1 | t t It t I a |. , 1 1 I . | is t a |-
t ir t a rir m a Ia r I Ia r t Iit r s a s a | a
I
-ir 1 t j t r 1 t r I j | t s- | t a r 1 K | -k 1 a s a ti1 | a s I| t t t r st r sa s K | -k siIt
Irt m I| t IL-2 j rt m t It r, | t rt a s r t | ir 1 ir ] a s 1 t - j | a Ia st | a I rt Ia ir s st r siIitiI It | sk a r 1 | | ! 1 t . k s
s| t r ir | i] a rt 1 k , I| t BNP j rt m t It r a s a t Iita It 1 It t It 1 It I| t 1 I I t r I I siIt s | i] a rt 1 | .
t t t r Iirm I| a I K | -k 1 Irt m t a r1 it m t t It s t t a |1 ] rt a It r I| a r 1 1 -It |1 ir I| t j rt st r t t t I | k k \ , K | -
k 1 , a r 1 t a |t ir t a rir . | k k \ a |t r t a s a |st a | |t It a |st | ir 1 I| t 1 I I siIt Irt m I| t BNP j rt m t It r, t a st 1
t a r1 ia t j rt It ir t t Ira t Is ir a ] t | m t | i|iI s| iII a ssa iI| a t Iita It I| is j rt m t It r, a s rt j t rIt 1 j rt tit a s| | rt j ir
t I a |. , 1 1 \ , | a I I| t t t It r I t I a t Iita Iit r a s |t ss I| a r I| t 1 I I siIt a s a j rt | t . | a r1 ia t t t Ira t I ] a tt rist
It m a |Iij |t t t m j |t t t s I| a I t t a |1 | t t |im ir a It 1 ir I| t t r t -It r I| I| a I | t r K | -k 1 a r 1 t a |t ir t a rir t rt a |st
j rt st r I. ir t t | k k \ a r 1 K | -k 1 a rt t t j rt sst 1 ir j rt st r t t t I a r t t t t ss t I I| t sa m t a r |a | t |t 1 t |i] t r a t |t -
t Ii1 t t r | a st | a t r t t t t rrt sj t r 1 ir ] It I| t K | -k r t t r a Ia | ra I t a r1 it m t t It s, iI st t m s I| t a rt |im iIir ]
ir I| is Ij t t I Ira r sIt t Iit r a ssa , m a | ir ] iI r t t t ssa r siIt ir I| t IL-2 j rt m t It r 1 a Ia r t I s| t r , | a I r t I |
r t r sj t t iIit st | a t r t t s | i] a rt 1 | . | t t a r1 it m t t It It t t j rt ss I| t t t t ] t r t a s j rt It ir s It st t I| t m a t im a |
rt sj t r st t I I| t BNP j rt m t It r. t t m j |t t t t a |1 a |st | t |a r] t | t |im ir a It 1 a sir ] a r K | -
k 1 -sj t t iIit a r Ii| t 1 |a r t ! . | itt r I| t 1 ra m a Iit rt sj t r sitt r t ss t I I| t BNP j rt -
m t It r It K | -k 1 , t t t a m ir t 1 I| t 1 1 | j j rt m t It r t 1 t It rm ir t | t I| t r I| t 1 I I siIt a s rt | a irt 1 It r
Ira r st rij Iit r a | a t Iita Iit r | K | -k 1 , t m a Ia It 1 I| is rt ] it r a st 1 ir I| t a | t tt Ira r sIt t Iit r a ssa s It r j t -
It r Iia | K | -k t t r st r sa s | ir 1 ir ] siIt s | | kkkk . | rt t siIt a r 1 It a r 1 I| a I I| t m a Ia r I j rt m t It r a s ir st r siIitt
It K | -k 1 | i] a rt 1 k . | t st rt sa |Is 1 t m t r sIra It I| a I st | a t r t t s rt |a It 1 It I| is siIt t rt i1 t r IiIit 1 a I 1 I I
| | k k k k | k k , 1 I I | | k k k k | | | , a r 1 I I k | | I| t BNP j rt m t It r is a 1 irt t I Ira r st rij Iit r a | Ia r] t I It r
sr t r] isIit a t Iita Iit r | | k k \ a r 1 K | -k 1 ir t a r1 it - k k k k k | . | t I I siIt a |st | ir 1 s | k k \ a r 1 is rt -
| a irt 1 It r BNP t t j rt ssit r | rt j ir t I a |. , 1 1 \ . | sir ] m t t It s.
| t ||
I I 1
a | |t . a m m a r t I -M 1 | -| a |t ir t a rir ra r s] t r it | ir t s
ra r s] t r it | ir t ra r s] t r t | t j | a a st t I | t a I| k ] t a I | t a I| 1 t a rI wt i] | I ] . I| t r Irt | | a r1 ia t | | t r t Ij t
\ t a t riIit t 1 1 a s I . I 1 j t rIrt j | it
I I I I a 1 1 t r 1 t t | s I . 1 | i|a It 1
1 1 a 1 1 t r \ t t | s I . t 1 j t rIrt j | it
1 t I a 1 1 t r 1 t t | s K | K |
1 1 Ii|| a |itt \ t t | s
\ t Ii|| a |itt I \ t t | s
1 I ! Ii|| a |itt I 1 t t | s
1 I - ! a t riIit t 1 ! t t | s I . 1 1 j t rIrt j | it
1 I -I ! a 1 1 t r \ t t | s K | 1 j t rIrt j | it
1 I -1 ! a 1 1 t r 1 t t | s I . ! 1 j t rIrt j | it
1 I -\ ! Ii|| a |itt t t | s
1 I -! ! Ii|| a |itt t t | s
1 I -t ! a 1 1 t r I t t | s I . 1 | i|a It 1
1 1 1 a 1 1 t r t t | s I . I 1 j t rIrt j | it
1 1 - 1 a 1 1 t r 1 t t | s K | 1 j t rIrt j | it
1 1 -I 1 a 1 1 t r \ t t | s K | K |
1 1 -1 1 Ii|| a |itt 1 t t | s
1 t a rI t i] | Is t rt 1 t It rm ir t 1 a r 1 a rt t t j rt sst 1 a s I| t rt |a Iitt t i] | I t I I| t Ira r s] t r it | t a rI t t m j a rt 1 It r t r Ira r s] t r it |iIIt r m a It s.
k ] t s t I m it t I| a I a rt sIi|| a |itt a rt s| t r ir j a rt r I| t st s a s t I I I I1 . 1 I a r 1 1 1 t rt It a r 1 t r Ira r s] t r it s a r 1 , m it t 1 t si] r a It 1 a s 1 I -
a r 1 1 1 - t rt I| t ir t IIsj rir ] . K | , r t I 1 t It rm ir t 1 .
CsA and FK506Inhibit the Hypertrophic Inductionof Cardiac Hypertrophy InVivo
Effects of AngII andPE byActivated Calcineurin
| t j t sa rt t I j rim a r t a r1 it m t t It s It k r ] | | a r 1 | | t 1 t It rm ir t | t I| t r I| t t a |t ir t a rir si] r a | Ira r s1 a t -
rt sa |Is ir a r ir t rt a st ir ir Ira t t ||a |a r | a
I
a r 1 a | j t rIrt - Iit r j a I| a t t a |1 a |st t j t ra It ir I| t m t t a r1 ia m ir
j | it rt sj t r st . t 1 t It rm ir t | t I| t r I| t | j t rIrt j | it titt , t ] t r t ra It 1 Ira r s] t r it m it t I| a I t t j rt sst 1 I| t
rt sj t r st t I t a r1 it m t t It s It I| t st a ] t r isIs a s m t - t t r sIiIa Iitt | a t Iitt It rm t I I| t t a |t ir t a rir t a Ia |Iit
1 ia It 1 | t a |t ir t a rir , t t t j t st 1 r t t r a Ia | ra I t a r1 it - sa | a r iI ir I| t | t a rI, a sir ] I| t -MHC j rt m t It r It 1 ritt
m t t It s It k r ] | | 1 r M t r | | 1 M ir I| t j rt st r t t
t t j rt ssit r . | rt tit a s sIa 1 it s | a tt s| t r I| a I I| is t a r-
a r 1 a | st r t t t I | sk t r | | ! 1 t . | a r1 it m t t It s 1 t m t r -
1 ia t -sj t t iIit j rt m t It r is a t Iitt ir I| t tt r Irit a |a r t | a m -
sIra It 1 a 1 ra m a Iit ir t rt a st ir sitt a r 1 sa rt t m t rit a s-
| t rs j rim a ri| a IIt r | irI| ! t r t s t I a |. , 1 1 \ . k It Ia | t I It r
st m | | a IIt r I I | r t I t t j t sa rt It k r ] | | t r | | | i] a rt s
ir 1 t j t r 1 t r I It a r 1 t r Ira r s] t r it m it t t rt ] t r t ra It 1 ,
\ | a r 1 \ | . | r I| t j rt st r t t t I | sk | i] a rt s \ | a r 1 \ |
| it | t t r Ia ir t 1 | t I t t r I a r 1 t t t j it s t I I| t -M 1 | -
t r | | ! 1 t 1 a Ia r t I s| t r , I| t rt sj t r st It k r ] | | a s
t a |t ir t a rir Ira r s] t r t a | |t .
t t m j |t It | a | t |is| t 1 a r 1 I| t rt sj t r st It | | a s 1 ra -
| tt r t a |t ir t a rir Ira r s] t r it m t a st a r a |tt 1 s| t t 1
m a Iit a || rt 1 a t t 1 .
a 1 ra m a Iit ir t rt a s t ir | t a rI sitt rt |a Iit t It r t r Ira r s-
t 1 t It rm ir t | t I| t r t | a r ] t s ir t a r1 it m t t It ] t r t
] t r it |iIIt rm a It s. | t | t a rI-It -| t 1 t i] | I ra Iit a tt r-
t t j rt ssit r ir rt sj t r st It k r ] | | t rt a |st t t r Irt ||t 1 |
a ] t 1 I - It 1 -It |1 ] rt a It r ir I| t t a |t ir t a rir Ira r s] t r it s
a t a |t ir t a rir -1 t j t r 1 t r I si] r a |ir ] j a I| a , t t t a m -
t t m j a rt 1 It t t r Irt | |iIIt rm a It s, t tt r a s t a r| a s
ir t 1 | 1 t I | |t I a ssa I| t t t j rt ssit r t I ANF m | K k ir
1 a s j t sIr a Ia || | i] a rt ! , a | |t . 1 isIt |t ] it a | a r a |sis
t a r1 it m t t It s Irt a It 1 iI| k r ] | | ir I| t j rt st r t t a r 1
s| t t 1 t t r t t r Irit | j t rIrt j | | t rt ir I| t t rt ss st t -
a | st r t t t I | sk . | t j t sa rt It k r ] | | rt sa |It 1 ir a ! -It |1
Iit r a | a rt a s t I I| t tt r Irit a |a r a ||s a r 1 ir It rtt r Irit a |a r
ir t rt a st ir ANF m | K k , | it | a s t t m j |t It | | |t t | t 1
st j Ia m t rt 1 ra m a Iit a || ir t rt a st 1 | i] a rt ! | . | t
| | sk | i] a rt \ | . GAPDH m | K k a s m t a sa rt 1 a s a
|t II tt r Irit |t a s m t sI a IIt t It 1 , | a I I| t ri] | I tt r Irit |t
t t r Irt |. t ] t I| t r, I| t st m t rj | t |t ] it a r 1 m t |t t a |a r
a r 1 I| t a Iria | t | a m | t rs t rt a |st t r |a r] t 1 . | r t t r Ira sI
1 a Ia 1 t m t r sIra It I| a I I| t k r ] | | a r 1 | | | j t rIrt j | it
It I| t t ||-t r] a r itt 1 , sIria It 1 m a st a |a Ia rt t I I| t r t rm a |
s i] r a |ir ] j a I| a s a rt | sk-I| | ! 1 t -s t r siIit t a r 1 I| t rt -
tt r Irit a |a r a ||, t a r1 it m t t It s Irt m I| t t a |t ir t a rir
It rt ir tt |tt t a |t ir t a rir a t Iita Iit r .
Ira r s] t r it | t a rIs t rt 1 ist r] a r itt 1 a r 1 t | tit a s| | -
| I K | -k a t Iita Iit r m t 1 ia It s | a
I
-1 t j t r 1 t r I | j t r-
j t rIrt j | it | i] a rt s ! | a r 1 ! | . | t | j t rIrt j | it t a r1 it -
Irt j | it si] r a |ir ] , I| t r k r ] | | a r 1 | | t a |1 | t t t j t t It 1
m t t It s t IIt r | a 1 1 ra m a Iit | a rt m t ] a |. M t a sa rt -
It ir 1 a t t K | -k a t IitiI. t It sI I| is, t Ira r sIt t It 1
m t r I t I t rt ss st t Iit r a | a rt a s t I m t t It s iI| ir I| t |t II
j rim a r ra I t a r1 it m t t It s iI| a r K | -k -1 t j t r 1 t r I
tt r Irit a |a r a || s| t t 1 a ] rt a It r I| a r I -It |1 ir t rt a st ir
luciferase rt j t rIt r t t r Ia ir ir ] I| rt t t t j it s t I I| t K | -
t a |t ir t a rir Ira r s] t r it s t t m j a rt 1 It t t r Irt |s 1 a Ia r t I
k t t r st r sa s st | a t r t t |ir | t 1 It I| t I| m i1 ir t | ir a st
s| t r .
m ir im a | j rt m t It r. | r I| t j rt st r t t t I k r ] | | 1 r M t r
|r | a m a r s, t a r1 ia t | j t rIrt j | Irt | a t r I| j rt ] rt s st s | | 1 M , rt j t rIt r ] t r t t t j rt ssit r a s a j -rt ] a |a It 1
It tt r Irit a |a r 1 i|a Ia Iit r , | t a rI Ia i|a rt , a r 1 sa 1 1 t r 1 t a I| . | i] a rt \ 1 . | is a j -rt ] a |a Iit r a s t t m j |t It | a | t |-
im i|a r|, ir t a |t ir t a rir Ira r s] t r it m it t , t t | st rtt 1 is| t 1 ir I| t j rt st r t t t I | sk t r | | ! 1 t , sa j j t rIir ] I| t
1 i|a Ia Iit r t I I| t tt r Irit a |a r t | a m | t rs iI| ir t rt a sir ] t t r t |a sit r I| a I k r ] | | a r 1 | | a t Iita It K | -k I| rt a ] | a
t a |t ir t a rir -1 t j t r 1 t r I si] r a | Ira r s1 a t Iit r j a I| a . a ] t | i] a rt s ! | a r 1 ! | . | a |t ir t a rir Ira r s] t r it m it t
| t ] a |a Iit r t I | a r1 ia t 1 j t rIrt j | | | a |t ir t a rir
I I
| i] a rt ! . 1 j t rIrt j | t I -M 1 | -| a |t ir t a rir
ra r s] t r it 1 t a rIs
k | t r Irt | a r 1 -M 1 | -t a |t ir t a rir Ira r s-
] t r it |iIIt rm a It s t rt sa t riIit t 1 a I 1 a s
t I a ] t a r 1 | t a rIs t rt rt m t tt 1 a r 1 j | t It -
] ra j | t 1 . | a r 1 | 1 t a rIs s| t r ir k t rt
st t Iit r t 1 |t r ] iIa 1 ir a ||. | t |t II tt r Irit a |a r
a || a r 1 st j Ia m a rt t t It r sitt | | j t rIrt -
j | it 1 ir I| t t a |t ir t a rir Ira r s] t r it | . | a r 1
| 1 i] | m a ] r iIit a Iit r tit s t I |t II tt r Irit a |a r
a ||s t I | t a rIs s| t r ir | a r 1 | , rt sj t t -
Iitt |. | a r 1 | ra r stt rst st t Iit r s I| rt a ] |
| t a rIs t I t t r Irt | a r 1 t a |t ir t a rir Ira r s] t r it s
a I 1 t t | s t I a ] t sIa ir t 1 iI| 1 a r 1 | . | t
t a |t ir t a rir Ira r s] t r it 1 it 1 sa 1 1 t r | a r 1
s| t s | j t rIrt j | a r 1 1 i|a Ia Iit r . 1 t t -
Iit r s Irt m I| t t a |t ir t a rir Ira r s] t r it | t a rI
s| t r ir | t rt sIa ir t 1 iI| M a sst r Iri-
t | rt m t It rt tt a | t t ||a ] t r . K t It I| t t t It r sitt
ir It rsIiIia | t t ||a ] t r 1 t j t siIs sa rrt a r 1 ir ] 1 t -
] t r t ra It 1 t a r1 it m t t It s. | a , t t rt r a r a r-
It r, |a , |t II a Iria m , |t, |t II tt r Irit |t , ra , ri] | I
a Iria m , rt, ri] | I tt r Irit |t . | a rs ir | , | , | ,
| , a r 1 1 m . | a rs ir | a r 1 |
! 1 m .
t rt a |st | i] | | sa st t j Ii| |t It sa 1 1 t r 1 t a I| . | is t t - 1 t r -rt ] a |a It 1 1 a rir ] | t a rI Ia i|a rt , a s I| t Ia i|ir ] m t -
t a r1 ia m t t | i| iIs 1 t It t Iitt | a
I
| a r 1 |ir ] t | ir ] t r t I t a rrt 1 sj t r Ia r t t a s|, a s t || a s 1 a rir ] | a r 1 |ir ] t r a r -
t sI| t sia . | t m it t I| a I 1 it 1 Irt m sa 1 1 t r 1 t a I| s| t t 1 a |. , 1 1 ! , | t I| Ira r st rij Is t rt 1 t t rt a st 1 ir t a |t ir t a rir
Ira r s] t r it s. | t rt a s r t si] r iIit a r I t | a r ] t ir GAPDH ri] | I a r 1 |t II tt r Irit a |a r 1 i|a Ia Iit r ir 1 it a Iitt t I | t a rI
Ia i|a rt . 1 isIt |t ] t I I| t |a r ] s a |st rt tt a |t 1 t t It r sitt t t j rt ssit r .
j t rit a st a |a r t 1 t m a a r 1 ir Ira a |t t t |a r m a t rt j | a ] t s t t r -
Ia ir ir ] rt 1 | |t t 1 t t ||s 1 a Ia r t I s| t r , Iir 1 ir ] s t t r sis-
Induction of Cardiac HypertrophyIn Vivo
It r I iI| | t a rI Ia i|a rt . 1 r t t I I| t | a ||m a r| s t I | t a rI
by Activated NF-AT3
Ia i|a rt is Ii| rt sis t I I| t tt r Irit a |a r a ||. | t | t a rIs t I w| i|t a t Iita Iit r t I K | -k 1 j rt It ir s is a t ||-t | a ra t It r-
t a |t ir t a rir Ira r s] t r it s t t r Ia ir t 1 t t It r sitt , j rim a ri| itt 1 m t t | a r ism t I a t Iit r t I t a |t ir t a rir ir t t ||s, a r 1
ir It rsIiIia |, 1 t j t siIs t I t t ||a ] t r , a s rt tt a |t 1 | Iri- K | -k a s a | |t It sr t r] itt iI| | k k \ a r 1 t a |t ir t a rir
t | rt m t sIa ir ir ] | i] a rt ! 1 . | r It t i iI| m a r| t 1 Ii| rt sis, It a t Iita It I| t BNP j rt m t It r ir t a |Ia rt 1 t a r1 it m t -
m t Ii| t r 1 t ] t r t ra Iit r a s t ti1 t r I. t It s, iI a s It rm a || j t ssi| |t I| a I I| t | j t rIrt j | it
rt sj t r st It t a |t ir t a rir ir titt t t a |1 ir tt |tt a K | -k -
ir 1 t j t r 1 t r I m t t | a r ism . t 1 t It rm ir t | t I| t r a t Ii- Activationof the Molecular Response to
HypertrophyIn Vivo byCalcineurin ta It 1 K | -k 1 t t a |1 sa | sIiIa It It r a || a j sIrt a m t |t m t r Is
ir I| t | j t rIrt j | it si] r a |ir ] t a st a 1 t , t t rt a It 1 a wt a st 1 a | a a r IiIa Iitt 1 t I | |t I a ssa It t t a m ir t | K k
Irt m | t a rIs t I t a |t ir t a rir Ira r s] t r it a r 1 r t r Ira r s] t r it t t r sIiIa Iitt | a t Iitt K | -k 1 m a Ia r I | 1 t |t Iir ] I| t
K -It rm ir a | rt ] a |a It r 1 t m a ir . | is m a Ia r I, rt It rrt 1 It |iIIt rm a It s It 1 t It rm ir t | t I| t r a t Iita It 1 t a |t ir t a rir
ir 1 a t t 1 t | a r ] t s ir t a r1 ia t ] t r t t t j rt ssit r t | a ra t It r- a s K | -k 1 1 I , |a t | t 1 I| t IirsI 1 I a m ir t a t i1 s t I I| t
j rt It ir | a I rt Ia ir t 1 I| t | t | | t m t |t ] a r 1 Ira r sa t Iita - isIit t I | j t rIrt j | a r 1 | t a rI Ia i|a rt . | t r sisIt r I iI|
rt a t Iita Iit r t I I| t It Ia | j rt ] ra m t I ] t r t t t j rt ssit r , Iit r 1 t m a ir s | i] a rt I k .
w| t r K | -k 1 1 I a s t t j rt sst 1 ir Ira r sIt t It 1 t a r- -MHC, -skeletal actin, a r 1 BNP Ira r st rij Is t rt 1 ra -
m a Iit a || a j -rt ] a |a It 1 ir Ira r s] t r it | t a rIs, | t rt a s 1 it m t t It s, iI | t t a m t t t r sIiIa Iitt | |t t a |itt 1 It I| t
r a t |t a s, ir t t r Ira sI It I| t i|1 -Ij t j rt It ir , | it | rt - -MHC a s 1 t r -rt ] a |a It 1 | i] a rt t . ra r st rij Is It r
sa rt t j |a s m it rt Iit a |a m | a
I
-k | a st SERCA a r 1 j | t s - | a irt 1 t a |t ir t a rir si] r a |ir ] It r r a t |t a r |t t a |ita Iit r | i] -
a rt s I | a r 1 I | . | t K | -k 1 1 I m a Ia r I a |st a t Iita It 1 j | t |a m | a r PLB | a tt | t t r s| t r j rt tit a s| It | t
| t ||
I I I
| i] a rt t . | | a r ] t s ir | a r1 ia t | t r t | t j rt ssit r ir -M 1 | -| a |-
t ir t a rir ra r s] t r it M it t
t Ia | | K k a s ist |a It 1 Irt m | t a rIs t I t t r Irt | a r 1 -M 1 | -t a |-
t ir t a rir Ira r s] t r it m it t a I t t t | s t I a ] t . | t ir 1 it a It 1 Ira r st rij Is
t rt 1 t It t It 1 | 1 t I | |t I a r a |sis, a r 1 I| t ir |t tt |s ir Ira r s] t r it
| t a rIs rt |a Iitt It t t r Irt |s a rt s| t r .
I| t K | -k -1 t j t r 1 t r I rt j t rIt r t t r sIra t I ir Ira r sit r I
Ira r sIt t Iit r a ssa s 1 a Ia r t I s| t r . wt I| t rt It rt t t -
j rt sst 1 I| is m a Ia r I ir I| t | t a rIs t I Ira r s] t r it m it t ,
a r 1 t r t t r Irt | t I I| t -MHC j rt m t It r. | rt t ir 1 t j t r -
1 t r I It a r 1 t r Ira r s] t r it m it t t rt t | Ia ir t 1 , a r 1 a ||
s| t t 1 j rt r t a r t t 1 |t II a r 1 ri] | I tt r Irit a |a r t t r t t r Irit
| j t rIrt j | | i] a rt s I | a r 1 I | . | i| t I| t t a |t ir t a rir
Ira r s] t r it s, I| t tt r Irit a |a r a ||s t I I| t K | -k 1 1 I
Ira r s] t r it s s| t t 1 t t It r sitt Ii| rt sis, iI| m t Ii| t r
1 isa rra a r 1 t a r1 it m t t It t r |a r] t m t r I. | r t t r Ira sI,
| i] a rt I . 1 j t rIrt j | t I -M 1 | -K | -k 1 ra r s] t r it 1 t a rIs
t t j rt ssit r t I i|1 -Ij t K | -k 1 a r 1 t r t t r Irt | t I I| t
k Ira t Ia rt t I K | -k 1 a r 1 K | -k 1 1 I m a Ia r I. | 1 | , | t | | t m t |-
-MHC j rt m t It r 1 i1 r t I |t a 1 It | j t rIrt j | 1 a Ia r t I
t ] 1 t m a ir , | t ] , rt ] a |a It r 1 t m a ir . k m ir t a t i1 j t siIit r s a rt ir 1 i-
s| t r . | a s, a t Iita It 1 K | -k 1 a |t r t is sa IIit it r I It
t a It 1 .
sa | sIiIa It It r | a
I
si] r a |s ir I| t | t a rI a r 1 t tt | t a | a r 1 | | rim a r t a r1 it m t t It s t rt Ira r sIt t It 1 iI| Ia ||-|t r ] I|
NF-AT3 a r 1 NF-AT3317 m a Ia r I t | K k s, rt sj t t Iitt |, a r 1 t t ||s | j t rIrt j | it rt sj t r st ir titt .
t rt sIa ir t 1 iI| a r Ii-K | -k a r Ii| t 1 . NF-AT3 is |t t a |itt 1 It I| t
t It j |a sm | t rt a s NF-AT3317 is |t t a |itt 1 It I| t r a t |t a s.
Prevention of Cardiac Hypertrophywith CsA
| a r 1 | 1 t a rIs Irt m r t r Ira r s] t r it a r 1 K | -k 1 1 I |iIIt rm a It s
t | t ] ir It 1 t It rm ir t | t I| t r ir | i| iIit r t I t a |t ir t a rir
a I \ t t | s t I a ] t t rt st t Iit r t 1 |t r ] iIa 1 ir a || a r 1 sIa ir t 1 iI| 1
a t IitiI ir titt m i] | I | t a r t IIt t Iitt m t a r s t I j rt tt r Iir ]
a r 1 | . | a , |t II a Iria m , |t, |t II tt r Irit |t , ra , ri] | I a Iria m , rt, ri] | I
t a r1 ia t | j t rIrt j | , t It sIt 1 | t I| t r sa | t a Ia r t t a s
tt r Irit |t . | a rs ir | a r 1 | I m .
ir }t t Iit r t I | sk t t a |1 j rt tt r I t a r1 ia t 1 sIa r t Iit r ir
t a |t ir t a rir Ira r s] t r it m it t . | t r I| t st t t j t rim t r Is, t
m t Ii| t r 1 isa rra a r 1 st a IIt rt 1 t t ||s iI| j rt m ir t r I
a st 1 t i] | I Ira r s ] t r it |iIIt rm a It s Irt m a |iIIt r t I Ira r s -
| j t rt | rt m a Iit r a t |t i. w| t I| t r I| t st rt j rt st r I t t ||s
] t r it m t a st 1 I st t a | |t . | t a r Ira r s] t r t -j t siIitt
I| a I t rt a |rt a 1 | j t rIrt j | it a I I| t Iim t | sk a 1 m ir is-
t IIsj rir ] t rt ir }t t It 1 I it t 1 a i| iI| | sk I ! m ] I| ]
Ira Iit r a s ir iIia It 1 t r | t I| t r I| t rt a rt a It t t ||s I| a I
| t 1 t i] | I a r 1 It a r t rt ir }t t It 1 iI| tt | it |t a |t r t .
t st a j t 1 I| t t IIt t Is t I | sk i|| rt | a irt Ia rI| t r ir tt sIi] a -
| t a r r t r Ira r s] t r it |iIIt rm a It s t rt a |st Irt a It 1 iI|
Iit r . K t tt rI| t |t ss, | sk Irt a Im t r I j rt tt r It 1 ] rt ss t a r-
| sk It t t r Irt | It r j t It r Iia | It t it t IIt t Is t r t a r1 ia t a | -
1 ia t | j t rIrt j | a r 1 a sst t ia It 1 j a I| t |t ] ir rt sj t r st
r t rm a |iIit s ir 1 a t t 1 | | sk . | sk Irt a Im t r I a s ir iIia It 1
It a t Iita It 1 t a |t ir t a rir ir titt .
a I 1 1 a s t I a ] t a r 1 a r im a |s t rt sa t riIit t 1 t 1 a s
|a It r. k s s| t r ir | i] a rt , I| t | t a rIs t I tt | it |t -Irt a It 1
Discussion
a r im a |s t rt | i] | | | j t rIrt j | it a r 1 1 i|a It 1 | 1 a I ! ,
| t rt a s I| t st Irt m | sk -Irt a It 1 |iIIt rm a It s t rt r t I
1 a r rt sa |Is 1 t Iir t a r ir Ira t t ||a |a r j a I| a It r ir 1 a t Iit r
si] r iIit a r I| 1 iIIt rt r I ir sitt Irt m r t r Ira r s] t r it t t r -
t I t a r1 ia t | j t rIrt j | I| a I |ir | s | a
I
si] r a |ir ] ir I| t
Irt |s. | t m t a r | t a rI-It -| t 1 t i] | I ra Iit s It r t a |-
t It j |a sm iI| t | a r ] t s ir t a r1 ia t ] t r t t t j rt ssit r .
t ir t a rir Ira r s] t r it s t rt r t a r| 1 -It |1 |a r] t r I| a r I| t st
k t Iita Iit r t I I| is | j t rIrt j | it j a I| a t iI| t r ir I| t
t I | sk -Irt a It 1 Ira r s] t r it s a r 1 r t r Ira r s] t r it s. | sk
t It j |a sm t r ir I| t r a t |t a s, iI| a t Iita It 1 It rm s t I
Irt a Im t r I a |st j rt tt r It 1 Ii| rt sis t I I| t | t a rIs t I t a |-
t a |t ir t a rir t r K | -k 1 , rt sj t t Iitt |, rt sa |Is ir m t |t t a |a r t ir t a rir Ira r s] t r it s 1 a Ia r t I s| t r .
a r 1 j a I| t j | sit |t ] it t | a r ] t s ir I| t | t a rIs t I Ira r s- k I a t t ||a |a r |t tt |, I| t | j t rIrt j | it rt sj t r st t I t a r1 it -
] t r it m it t I| a I m im it I| t st a sst t ia It 1 iI| t a r1 ia t m t t It s ir I| t t a |t ir t a rir Ira r s] t r it s a s |a r] t | ir -
| i| iIt 1 | | sk , a |I| t a ] | I| t rt t rt ist |a It 1 a rt a s t I | j t rIrt j | a r 1 | t a rI Ia i|a rt ir | a m a r s.
| t ] a |a Iit r t I | a r1 ia t 1 j t rIrt j | | | a |t ir t a rir
I I 1
| i] a rt . | rt tt r Iit r t I | a |t ir t a rir -| t j t r 1 t r I 1 j t rIrt j | | | sk
k | t rt ] im t r It r | sk Irt a Im t r I is s| t r .
| -M 1 | -t a |t ir t a rir Ira r s] t r it | a r 1 r t r Ira r s] t r it m it t t rt Irt a It 1 iI| t r iI| t a I | sk I ! m ] I| ] | t 1 t i] | I , a s ir 1 it a It 1 . 1 t a rI-
It -| t 1 t i] | I ra Iit s a rt t t j rt sst 1 sIa r 1 a r1 1 t tia Iit r s. ra r s] t r it |iIIt rm a It s t | Ia ir t 1 Irt m m a |t t a |t ir t a rir Ira r s] t r it 1 I st t a | |t
t rt ir }t t It 1 sa | t a Ia r t t a s| I it t 1 a i| iI| | sk t r tt | it |t a |t r t | t ] ir r ir ] a I 1 1 a s t I a ] t . k I I ! 1 a s t I a ] t , a r im a |s t rt sa t riIit t 1
a r 1 | t a rIs t rt rt m t tt 1 a r 1 st t Iit r t 1 |t r ] iIa 1 ir a ||.
| 1 a r 1 | st t Iit r s t I | t a rIs Irt m r t r Ira r s] t r it t t r Irt | a r 1 Ira r s] t r it m it t Irt a It 1 iI| tt | it |t t t r It r j a r t | t r | sk ri] | I j a r t | . | a ,
|t II a Iria m , |t, |t II tt r Irit |t , ra , ri] | I a Iria m , rt, ri] | I tt r Irit |t . | t ri] | I a Iria m a s rt m t tt 1 Irt m I| t t t r Irt |, a r 1 | t I| a Iria t rt rt m t tt 1
Irt m I| t Ira r s] t r it Irt a It 1 iI| | sk . | a r I m .
Calcineurin, a Ca
2
-Sensitive Regulator m t 1 ia It r t I t a r1 ia t | j t rIrt j | ir rt sj t r st It t a |-
t ir t a rir a t Iita Iit r . K | -k a t IitiI a s ir 1 a t t 1 | of Hypertrophy
| I is t || t sIa | |is| t 1 I| a I t |t ta Iit r ir ir Ira t t ||a |a r | a
I
Irt a Im t r I t I t a r1 it m t t It s iI| k r ] | | a r 1 | | . | is
ir 1 a t Iit r a s | |t t | t 1 | | sk a r 1 | | ! 1 t , ir 1 it a Iir ] is a sst t ia It 1 iI| I| t ir iIia Iit r t I m t t | a r it a | t r a ] t r isI-
ir 1 a t t 1 t a r1 ia t | j t rIrt j | M a r| a r t I a |. , 1 I , | a s- I| a I iI is t a |t ir t a rir -1 t j t r 1 t r I. I K | -k 1 sr t r] itt 1
iI| | k k \ It a t Iita It I| t BNP j rt m t It r ir t a r1 it m t - Ia m a r It t I a |. , 1 1 , | t | a t r r t t t I a |. , 1 1 , a t | i t I
a |. , 1 1 1 , | t a rrt a a |I t I a |. , 1 1 \ , 1 t r ] t t I a |. , 1 1 ! . t It s. 1 | t j rt ssit r t I a t Iita It 1 K | -k 1 ir I| t | t a rI
a s sa IIit it r I It | j a ss a || a j sIrt a m t |t m t r Is ir I| t | t m a r| a | |, | t t tt r, I| t j t ssi| i|iI I| a I t a |t ir t a rir
m i] | I j a rIit ij a It ir I| t Ira r s1 a t Iit r t I | j t rIrt j | it | j t rIrt j | it si] r a |ir ] j a I| a a r 1 t tt | t a | j t rIrt -
j | it rt sj t r st . si] r a |s ir t a r1 it m t t It s | a s r t I | t t r a 1 1 rt sst 1 .
| a |t ir t a rir is a a | i| a iIt a s| t t j rt sst 1 st rir t II| rt t -
r ir t j | t sj | a Ia st I| a I t t isIs a s a | t It rt 1 im t r, t t m - Combinatorial Interactions between GATA
and NF-AT Proteins j rist 1 t I a ! 1 | | a t a |m t 1 a |ir -| ir 1 ir ] t a Ia |Iit k sa | -
a r iI a r 1 a 1 | | a | a
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-| ir 1 ir ] rt ] a |a It r | sa | a r iI 1 a r rt sa |Is 1 t m t r sIra It I| a I I| t | -It rm ir a | j t rIit r t I
I| t | t | | t m t |t ] 1 t m a ir t I K | -k 1 ir It ra t Is iI| I| t It m m t r a r 1 | |t t , 1 1 \ , a t I a |. , 1 1 ! . | a |t ir t a rir
is a r i| a t | sa iIt 1 It m t 1 ia It I| t j rt |t r ] t 1 | j t rIrt j | it st t t r 1 tir t Iir ] t r t I | k k \ , a s t || a s iI| | k k !
a r 1 | k k t , | it | a rt a |st t t j rt sst 1 ir I| t | t a rI. | t rt sj t r st t I a t a r1 it m t t It It | a
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si] r a |ir ] | t t a a st
I| t t r tm t is a t Iita It 1 | a sa sIa ir t 1 | a
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j |a It a a t rsIa | sIra t Ia rt t I I| t | K k | ir 1 ir ] rt ] it r t I K | -k t
| a s rt tt a |t 1 I| a I I| t | -It rm ir a | j t rIit r t I I| t | t | | t - a r 1 is ir st r siIitt It Ira r sit r I | a
I
I|a t t s sa t | a s t t t a r
ir rt sj t r st It t a r1 it m t t It t t r Ira t Iit r | t |m t Ist | m t |t ] 1 t m a ir j rt }t t Is a a Irt m I| t | K k -| ir 1 ir ]
siIt a r 1 a |st m t 1 ia It s ir It ra t Iit r iI| k | - ir im m a r t t I a |. , 1 1 I .
k t Iita Iit r t I t a |t ir t a rir is m t 1 ia It 1 | | ir 1 ir ] t I t t ||s wt |It t I a |. , 1 1 I .
w| a I is I| t si] r iIit a r t t t I I| t K | -k 1 -| k k \ ir It ra t - | a
I
a r 1 t a |m t 1 a |ir It I| t rt ] a |a It r a r 1 t a Ia |Iit sa | -
a r iIs, rt sj t t Iitt |. | rt tit a s sIa 1 it s s| t t 1 I| a I t tt r- Iit r It r a t Iita Iit r t I I| t | j t rIrt j | it rt sj t r st ! | t t j -
t ra Iitt a t Iita Iit r t I I| t BNP j rt m t It r | K | -k 1 a r 1 t t j rt ssit r t I t a |m t 1 a |ir ir I| t | t a rI a |st rt sa |Is ir
| j t rIrt j | , | a I I| t m t t | a r ism ir tt |tt 1 a s r t I 1 t It r- | k k \ rt | a irt s K | -k | ir 1 ir ] It a Ia r] t I st | a t r t t ir
I| t BNP a j sIrt a m rt ] it r . | rt tit a s sIa 1 it s | a tt 1 t m - m ir t 1 | ra tt r t I a |. , 1 1 1 . 1 a r rt sa |Is sa ] ] t sI I| a I
t a |m t 1 a |ir a t Is I| rt a ] | I| t t a |t ir t a rir j a I| a It ir - t r sIra It 1 I| a I | k k \ | ir 1 ir ] siIt s |t t a It 1 r t a r I| t
j rt t im a | BNP j rt m t It r a rt a |st rt | a irt 1 It r a t Iita Iit r 1 a t t I| t | j t rIrt j | it rt sj t r st .
| r t t ||s, m a r t I I| t t | a r ] t s ir ] t r t t t j rt ssit r t I I| t ] t r t | rt j ir t I a |. , 1 1 \ . | a s, t r I| is sj t t iIit
| j t rIrt j | it -rt s j t r sit t ] t r t , a r 1 j t r| a j s t I| t rs, I| t st ir rt sj t r st It t a |t ir t a rir a t Iita Iit r a rt m t 1 ia It 1 |
m t m | t rs t I I| t K | -k Ia m i| t I Ira r st rij Iit r Ia t It rs, Ia t It rs a t I t t m | ir a It ria || It a t Iita It Ira r st rij Iit r . K | -
k j rt It ir s rt ] a |a It t t rIa ir t t || ] t r t s | | ir 1 ir ] a | it | Ira r s|t t a It It I| t r a t |t a s It ||t ir ] 1 t j | t sj | t r-
|a Iit r | t a |t ir t a rir . | rt t ir 1 t j t r 1 t r I t | st rta Iit r s t t m j t siIt | K k st | a t r t t ir t t r }a r t Iit r iI| k | -
wt |It t I a |. , 1 1 I . | r I| t t a st t I I| t BNP j rt m t It r, sa j j t rI I| t t t r t |a sit r I| a I K | -k is a |st a r im j t rIa r I
| t ||
I I \
t | a tt r t t ti1 t r t t It r I| is Ij t t I }t ir I | K k | ir 1 ir ]
| t I t t r | k k \ a r 1 K | -k 1 , sir t t I| t | ir 1 ir ] siIt s It r
I| t st Ia t It rs a rt r t I im m t 1 ia It | a 1 }a t t r I a r 1 siIt s
It r | t I| Ia t It rs a rt rt | a irt 1 It r sr t r] isIit a t Iita Iit r .
M t rt t tt r, ir | K k | ir 1 ir ] a ssa s, t | a tt It a r 1 r t
t ti1 t r t t It r | ir 1 ir ] t I | k k \ a r 1 K | -k 1 It ] t I| t r It
t iI| t r Ij t t I siIt 1 a Ia r t I s| t r .
k ta rit I t I Ira r st rij Iit r Ia t It rs | a tt | t t r im j |it a It 1
ir t a r1 ia t | j t rIrt j | , ir t |a 1 ir ] | | - | a ria t I a |. ,
1 1 \ , | a rr s t I a |. , 1 1 ! , | | a 1 t s| im a a r 1 | ta m t ,
1 1 1 , a 1 t s| im a t I a |. , 1 1 1 , k | - | t ta t it -M i|itt }t tit
t I a |. , 1 1 t , a r 1 | k k \ 1 a st ] a a t I a |. , 1 1 I , 1 t rti]
t I a |. , 1 1 I . | r |i] | I t I I| t t t t j t ra Iit r | t I t t r K | -k
a r 1 k | - ir I| t t t r Irt | t I t t || ] t r t t t j rt ssit r , iI is
It m j Iir ] It sj t t a |a It I| a I a sim i|a r m t t | a r ism t t a |1
rt ] a |a It t t rIa ir t a r1 ia t ] t r t s ir rt sj t r st It | j t rIrt - | i] a rt 1 . k M t 1 t | It r I| t | a |t ir t a rir -| t j t r 1 t r I ra r st rij Iit r a |
| a I| a ir | a r1 ia t 1 j t rIrt j | j | . w| t I| t r K | -k ir It ra t Is iI| t r rt ] a |a It s I| t t t -
k r ] | | , | | , a r 1 j t ssi| | t I| t r | j t rIrt j | it sIim a |i a t Iir ] a I I| t t t || j rt ssit r t I t I| t r Ira r st rij Iit r Ia t It rs I| a I t t r Irt | t a r-
m t m | ra r t |t a 1 It t |t ta Iit r t I ir Ira t t ||a |a r | a
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a r 1 a t Iita Iit r t I
1 ia t ] t r t s a rra r Is Ia rI| t r ir tt sIi] a Iit r .
t a |t ir t a rir ir I| t t It j |a sm . | a |t ir t a rir 1 t j | t sj | t r|a It s K | -k 1 ,
it | k k Ira r st rij Iit r Ia t It rs | a tt | t t r i1 t r IiIit 1
rt sa |Iir ] ir iIs Ira r s|t t a Iit r It I| t r a t |t a s, | t rt iI ir It ra t Is iI|
ir tt rIt | ra It sj t t it s, t a t | t I | it | t t r Ia ir s a | i] | |
| k k \ It sr t r] isIit a || a t Iita It Ira r st rij Iit r . w| t I| t r a || a t Iit r s
t t r st rtt 1 | K k -| ir 1 ir ] 1 t m a ir t t r sisIir ] t I I t tir t
t I K | -k 1 a rt m t 1 ia It 1 | iIs ir It ra t Iit r iI| | k k \ t r | t I| t r
Iir ] t rs t I I| t m t IiI | s -X
I
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I
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I
-| s rt tit t 1 I| t rt a rt | k k \ -ir 1 t j t r 1 t r I j a I| a s It r a t Iita Iit r t I t t rIa ir
| j t rIrt j | it rt sj t r st s rt m a ir s It | t 1 t It rm ir t 1 . t |i1 a rrt s ir | ta r s, 1 1 I . | a st 1 t r st | a t r t t | t m t |t ] a r 1 t t -
1 t r t It j a I| a s I| a I a rt | r t r . | t IIt 1 |ir t s 1 t r t It j t ssi| |t j a I| -
j rt ssit r j a IIt rr s, I| t | k k j rt It ir s t a r | t 1 iti1 t 1
a s I| a I | a tt r t I | t t r 1 t m t r sIra It 1 .
ir It I t sa | Ia m i|it s. | k k II I1 a rt t t j rt sst 1 ir | t m a -
It j t it Iit t t ||s, | i|t | k k \ I! It a rt t t j rt sst 1 j rim a ri|
ir I| t | t a rI a r 1 ta st a |a r ssIt m , a s t || a s ir tis-
j a I| a s a 1 t s| im a a r 1 | ta m t , 1 1 1 , a 1 t s| im a t I
t t ra | t r 1 t 1 t rm a | 1 t rita Iitt s. | itt r I| t im j t rIa r t t t I
a |. , 1 1 1 , l t a t I a |. , 1 1 t , | a 1 t | t I a |. , 1 1 I , Ya m a ta | i | k k II I1 ir | t m a It j t it Iit t t ||s a r 1 I| t t ||-1 t t a -
t I a |. , 1 1 I . | sk 1 t t s r t I ir It rIt rt iI| t a r| si] r a |ir ]
m t r It 1 rt |t s t I K | -k j rt It ir s ir t t ||s, iI i|| | t
t tt r Is a I I| t t t || m t m | ra r t , sa t | a s | | Ia rr t tt r, | a
I
t I ir It rt sI It 1 t It rm ir t | t I| t r I| t st I t Ia m i|it s t I
m t | i|ita Iit r , t r | | | a t Iita Iit r | m m t | t I a |. , 1 1 .
Ira r st rij Iit r Ia t It rs t a r ir It ra t I ir I| t st t t ||s.
| a s, iIs a | i|iI It a | rt ] a It I| t | j t rIrt j | it rt sj t r st s
t I k r ] | | a r 1 | | sa ] ] t sIs I| a I t a |t ir t a rir a t Iita Iit r is
ATranscriptional Pathway for Cardiac Hypertrophy
a r t sst r Iia | sIt j ir I| t k r ] | | a r 1 | | si] r a | Ira r s1 a t Iit r
| rt tit a s sIa 1 it s | a tt 1 t m t r sIra It 1 im j t rIa r I rt |t s It r
j a I| a s.
| a s, M k | | ir a st , a r 1 | | | si] r a |ir ] j a I| a s ir I| t
1 a r rt sa |Is a rt t t r sisIt r I iI| a m t |t t a |a r j a I| a
| j t rIrt j | it rt sj t r st . k || t I I| t st si] r a | Ira r s1 a t Iit r
It r t a r1 ia t | j t rIrt j | a s s| t r ir | i] a rt 1 . k t t t r1 ir ]
j a I| a s a rt a sst t ia It 1 iI| a r ir t Irt j it ir t rt a st ir
It I| is m t 1 t |, | j t rIrt j | it sIim a |i sa t | a s k r ] | | a r 1
ir Ira t t ||a |a r | a
I
t t r t t r Ira Iit r . |r t t ||s, I| t t a |t ir t a -
| | , | it | |t a 1 It a r t |t ta Iit r t I ir Ira t t ||a |a r | a
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, rt sa |I
rir si] r a |ir ] j a I| a is a t Iita It 1 ir 1 t j t r 1 t r I| t I, | a I
ir a t Iita Iit r t I t a |t ir t a rir . K | -k 1 iI| ir I| t t It j |a sm
is ir It ] ra It 1 iI| , I| t | a sIM k | | ir a st a r 1 | | | j a I| -
is 1 t j | t sj | t r|a It 1 | t a |t ir t a rir , t r a | |ir ] iI It Ira r s-
a s. | a || ir 1 a t Iit r t I IL-2 Ira r st rij Iit r rt | a irt s t t -
|t t a It It I| t r a t |t a s | t rt iI t a r ir It ra t I iI| | k k \ .
sIim a |a Iit r tia I| t t a |t ir t a rir a r 1 | a s j a I| a s, | it |
w| i|t t a |t ir t a rir is t sst r Iia | It r k r ] | | - a r 1 | | -1 t j t r -
rt sa |I ir a t Iita Iit r t I K | -k a r 1 k | - , rt sj t t Iitt |,
1 t r I | j t rIrt j | ir tiIrt , a r 1 a t Iita Iit r t I t iI| t r t a |-
a r 1 I| t ir t t r tt r] t r t t t r a t t m m t r 1 t r sIrt a m Ia r] t I
t ir t a rir t r K | -k 1 is sa IIit it r I It t tt | t I| t | j t r-
st | a t r t t rt tit t 1 ir | a t t I a |. , 1 1 I . | is Ij t t I
Irt j | it rt sj t r st ir titt , iI is a |st t t r t t ita | |t I| a I
ir It ] ra It 1 si] r a |ir ] | t a rs t | tit a s sim i|a riIit s It I| t
t a |t ir t a rir t t a |1 a t I I| rt a ] | a r K | -k -ir 1 t j t r 1 t r I
m t t | a r ism s It rir 1 a t Iit r t I t a r1 ia t | j t rIrt j | . w| i|t
m t t | a r ism It rt ] a |a It | j t rIrt j | . | r 1 t t 1 , t a |t ir t a -
t a r rt sa |Is 1 t m t r sIra It I| a I I| t t a |t ir t a rir -K | k 1 si] -
rir t t a |1 j t It r Iia || | a tt t I| t r sa | sIra It s ir t a r1 it - r a |ir ] j a I| a is sa IIit it r I It ir 1 a t t | j t rIrt j | ir
m t t It s I| a I j |a rt ] a |a It r rt |t s ir | a
I
| a r 1 |ir ] t r titt , iI a |st st t m s |i| t | I| a I I| is j a I| a a r 1 I| t | a sI
Ira r st rij Iit r a | t t r Irt |. K | -k 1 t t a |1 a |st j t It r Iia || M k | | ir a st j a I| a m a | t ir It r1 t j t r 1 t r I ir t a r1 it -
a t Iita It st m t | j t rIrt j | it rt sj t r sitt ] t r t s, I| rt a ] | m t t It s, a s ir im m a r t t t ||s.
m t t | a r ism s ir 1 t j t r 1 t r I t I | k k \ . | is m t 1 t | a |st | sk a r 1 | | ! 1 t | ir 1 I| t im m a r t j | i|ir s t t |t j | i|ir
j rt 1 it Is I| a I j | t sj | t r|a Iit r t I I| t K -It rm ir a | rt ] a |a - a r 1 | | ! 1 t | ir 1 ir ] j rt It ir | | | | I , rt sj t t Iitt |,
It r siIt s ir K | -k 1 t t a |1 | t a | t rt ] a |a It r sIt j ir It rm ir ] t t m j |t t t s I| a I | ir 1 I| t t a |t ir t a rir t a Ia |Iit
I| t | j t rIrt j | it si] r a |ir ] j a I| a . | ir It rt r t t , a t Ii- sa | a r iI a r 1 ir | i| iI iIs a t IitiI. 1 a r rt sa |Is s| t I| a I
ta Iit r t I I| t K | -k | ir a st t a |1 | t t t j t t It 1 It ir It r- | sk a r 1 | | ! 1 t | |t t | I| t a | i|iI t I t a |Ia rt 1 t a r1 it m t -
It rt iI| | j t rIrt j | , | t rt a s iIs ir | i| iIit r t a |1 |t a 1 t It s It a r 1 t r] t | j t rIrt j | ir rt sj t r st It k r ] | | a r 1
It | j t rIrt j | . | | . | t I| t I I| t st | j t rIrt j | it a ] t r isIs | a tt | t t r
| t st sIa 1 it s a |st ra ist I| t j t ssi| i|iI I| a I a r K | - s| t r It a t I | t |t ta Iir ] ir Ira t t ||a |a r | a
I
, | it | rt -
sa |Is ir a t Iita Iit r t I I| t | | | a r 1 M k | | ir a st si] r a |ir ] k -1 t j t r 1 t r I m t t | a r ism t t a |1 t t r Irt | r t rm a | t a r1 ia t
| t ] a |a Iit r t I | a r1 ia t 1 j t rIrt j | | | a |t ir t a rir
I I !
t |t r t s a j j rt t im a It | I t rt rt Ira r sIt rm t 1 | a t | ir It t a sI It
] rt I| 1 a rir ] 1 t tt |t j m t r I. | r I| is rt ] a r1 , K | -k 1 is
It sI It r sj t t iIit iI. | rt t st j a ra It t riIt ria t rt st I It r 1 t It rm ir a Iit r
t t j rt s st 1 ir t a r1 it m t t It s iI| ir I| t t m | r t r it | t a rI
t I sj t t iIit iI. | irsI, I| t ist |a It 1 t |t r t s | a 1 It rt t a j iIa |a It I| t ir It r-
! . | . M . a r 1 | . K . 1 . , a r j a | |is| t 1 1 a Ia .
a t Iit r . t t t r 1 , I| t ist |a It 1 t |t r t s t t a |1 r t I ir It ra t I iI| a r t r sj t -
t iIit | a iI, ir I| is t a st a | k | \ -| I Ia sit r . | ir1 , t t | t st It It t a s
Calcineurinand NF-AT3Transgenic Mice
ir iIia || t r Ia t It rs I| a I t t a |1 a |st ir It ra t I iI| | k k ! , sir t t I| t rt
is ] rt a It r I| a r 1 I X a m ir t a t i1 t t r st rta Iit r iI| ir I| t tir t Iir ] t r as Models for Dilated Cardiomyopathy
1 t m a ir s t I | k k \ a r 1 | k k ! . | t NF-AT3 j rt t |t r t Ia |Ii||t 1
and Heart Failure inHumans
I| t st t riIt ria .
| t rt sa |Is t I I| is sIa 1 ra ist I| t j t ssi| i|iI I| a I t a |t i-
| t rt st a t 1 NF-AT3 t | K k Ira ] m t r I a s a |st sa | t |t r t 1 a s a
r t a rir a t Iita Iit r m a rt ] a |a It | j t rIrt j | ir rt sj t r st
X| t | Ira ] m t r I ir It I| t a || siIt t I I| t m a m m a |ia r | k | \ Ia sit r
It a ta rit I t I j a I| t |t ] it sIim a |i a r 1 sa ] ] t sI a st r sir ]
j |a sm i1 j M a r 1 It sIt 1 It r a t Iita Iit r t I I| t | k | \ -1 t j t r 1 t r I rt -
m t t | a r ism It r a |It rt 1 sa rt t m t rit Ia r t Iit r . 1 I r t It ,
j t rIt r. M t I| t 1 s It r t a |Ia rir ] a r 1 Ira r sIt t Iit r t I 1 II t t ||s a |t r ]
iI| I| t a r a |sis t I | k a t IitiI t rt 1 t st ri| t 1 j rt tit a s| M t || t r - I| t rt a rt st tt ra | Ia m i|ia | | j t rIrt j | it t a r1 it m t j a I| it s
Iir t I a |. , 1 1 t .
| 1 | t a a st 1 | m a Ia Iit r s ir t t r Ira t Ii|t j rt It ir ] t r t s,
| it | rt sa |I ir sa | I|t 1 ist r] a r ita Iit r ir I| t Iir t t rsIa |-
In Vitro Translationand Immunoprecipitation
|ir t -|i| t sIra t Ia rt t I I| t sa rt t m t rt wa I| ir s t I a |. , 1 1 ! ,
| t j a rIia | NF-AT3 t | K k rt ] it r rt st a t 1 Irt m I| t I t -| | ri1 j rt
Vi| sIrt m a r 1 | t ir a r 1 , 1 1 t . | I is a r | r t r | t sa rt t -
j |a sm i1 a s sa | t |t r t 1 a s a r X| t | Ira ] m t r I ir It I| t a || siIt t I
m t rit 1 ist r] a r ita Iit r is st r st 1 | I| t t a r1 it m t t It ,
I| t pECE-Flag m a m m a |ia r t t j rt ssit r tt t It r. t ] t r t ra It a tt t It r
| a I iI is a j j a rt r I I| a I I| is |t a 1 s It a |It rt 1 | a
I
| a r 1 |ir ] sa iIa | |t It r ir tiIrt Ira r s|a Iit r , I| t NF-AT3 t | K k Ira ] m t r I a |t r ]
iI| I| t ! | |a ] t j iIt j t a s t t t ist 1 Irt m j | | | -| |a ] -K | -k 1 a s | ir t I a |. , 1 1 t , | t Iir t ||i t I a |. , 1 1 I , | a |m iIt ra r 1 t |a rt ,
a K t I| -X| a | Ira ] m t r I a r 1 t |t r t 1 ir It I| t j | iIt I | I j rt m t It r-
1 1 I . | a |t ir t a rir t t a |1 rt j rt st r I I| t st r sir ] m t |t t a |t
t t r Ia ir ir ] ir tiIrt Ira r st rij Iit r tt t It r | r tiIrt ] t r . | is a ||t t 1 It r
I| a I t t a j |t s a |It rt 1 | a
I
| a r 1 |ir ] a sst t ia It 1 iI| | 1 |
I| t ] t r t ra Iit r t I a 1 I a m ir t a t i1 K | -k 1 -| |a ] Ia sit r j rt It ir . a || -
iI| t a r1 ia t | j t rIrt j | a r 1 | t a rI Ia i|a rt .
X| a | Ira ] m t r Is t t rrt sj t r 1 ir ] It I| t 1 t r t It 1 a m ir t a t i1 s ir | k k \
| t -M 1 | -t a |t ir t a rir Ira r s ] t r it m it t a |st rt j rt s t r I
t rt sa | t |t r t 1 It ] t r t ra It j | iIt I k -| k k \ 1 \ \ , j | iIt I k -
a m t 1 t | ir | it | It ir tt sIi] a It I| t j t It r Iia | rt tt rsi| i|iI | k k \ \ \ , j | iIt I k -| k k \ I 1 1 \ \ , j | iIt I k -| k k \ 1 1 I ,
j | iIt -| k k \ 1 I , a r 1 j | iIt I k 1 \ \ I1 I t ! I 1 \ . k t | K k Ira ] - t I t a r1 ia t | j t rIrt j | a r 1 I| t a rt | iIt t Ia ra | t | a r ] t s
m t r I t r t t 1 ir ] a m ir t a t i1 s 1 1 1 ! 1 t I m t a st | k k t a s a |st
a sst t ia It 1 iI| | t a rI Ia i|a rt | t t a a st I| t | j t rIrt j | it
t |t r t 1 a s a a || -X| a | Ira ] m t r I ir It j | iIt I k . | r a 1 1 iIit r , a I j rt -
t IIt t It r m t |t t a |t t a r | t ir | i| iIt 1 j | a rm a t t |t ] it a ||.
m t It r-1 irt t It 1 t t r sIra t I t r t t 1 ir ] I| t t r Iirt | t | | t m t |t ] 1 t m a ir
ir t t I| t st m it t a |Iim a It | j rt ] rt ss It 1 i|a It 1 t a r1 it -
t I I| t | a m a r K | -k 1 j rt It ir a m ir t a t i1 s \ 1 \ t 1 \ a s a st 1 ir
m t j a I| , Irt a Im t r I iI| | sk a I I| t st |a It r sIa ] t s i||
I| t st sIa 1 it s ] iII Irt m | r. . 1 t t 1 t t t I a |. , 1 1 ! .
sa ] ] t sI I| t 1 t ] rt t It | it | j a I| t |t ] it a | t t r 1 iIit r s | t a j |t 1 ir tiIrt Ira r st rij Iit r a r 1 Ira r s|a Iit r Irt m I| t I j rt m t It r
a s j t rIt rm t 1 ir I| t j rt st r t t t I
1 !
-m t I| it r ir t a t t t r1 ir ] It I| t a r 1 sIra t Ia ra | a |It ra Iit r s a sst t ia It 1 iI| I| t | j t rIrt -
K | iI j rt It t t | | rt m t ] a , M a 1 ist r , w| . | m m a r t j rt t ij iIa Iit r s
j | it rt sj t r st a rt rt tt rsi| |t .
t rt 1 irt t It 1 a ] a ir sI I| t | |a ] t j iIt j t a sir ] | |a ] a r Ii| t 1 | t 1 a |
| t st rt sa |Is a |st ra ist I| t | a t sIit r | t I| t r | sk
| | | , K t 1 a tt r , | | i] a rt s I k a r 1 I | t r a ] a ir sI I| t | t | | t m t |t ]
t r | | ! 1 t m i] | I | t a st Ia | ir I| t Irt a Im t r I t I t a r1 ia t
1 t m a ir t I K | -k 1 a r Ii| t 1 1 t st ri| t 1 ir | a | | t I a |. , 1 1 I | i] a rt
| j t rIrt j | a r 1 | t a rI Ia i|a rt ir | a m a r s. | t st im m a r t -
I | . | r tiIrt Ira r st rij Iit r -Ira r s|a Iit r a s j t rIt rm t 1 ir a rt a t Iit r
sa j j rt ssa r Is a rt a st 1 rt a Iir t | ir Ira r sj |a r I j a Iit r Is tt |a m t t I I ! | iI| 1 . ! ] t I t a t | t t r sIra t I. | itt m it rt |iIt rs t I
I| is rt a t Iit r m it a s im m a r t j rt t ij iIa It 1 a t t t r1 ir ] It I| t m a r a - It j rt tt r I Iissa t rt }t t Iit r , | a I t |ir it a | 1 a Ia t t rrt |a Iir ]
Ia t Ia rt rs rt t t m m t r 1 t 1 t t r 1 iIit r s | t 1 a | | | | , K t 1 a tt r , | ir
| sk Irt a Im t r I iI| t a r1 ia t Ia r t Iit r ir Ira r sj |a r I j a -
a It Ia | tt |a m t t I 1 1 | iI| I | t I a r Ii-| | k | m t r t t |t r a | a r Ii| t 1 ,
Iit r Is a rt ir t t r t |a sitt 1 a tt rit | t I a |. , 1 1 \ . 1 t t tt r,
t r ! | t I K | -k 1 -sj t t iIit a r Ii| t 1 It ] t I| t r iI| I ! | t I j rt It ir -
iI | a s | t t r rt j t rIt 1 ir a sIa 1 t I | t a rI Ira r sj |a r I j a -
k I| a ] a rt st . | t j rt t ij iIa It 1 j rt 1 a t Is t rt a r a |tt 1 | | -
Iit r Is I| a I | sk ir t rt a st s t a r1 ia t Ia r t Iit r a r 1 |t II tt r -
| k | | a r 1 a a It ra 1 it ] ra j | .
Irit a |a r t }t t Iit r Ira t Iit r a r 1 rt sa |Is ir It t r ist | t m it
t j ist 1 t s | t i1 a r 1 Ya t t a | , 1 . | itt r I| t rt m a r| a | |t Preparation of PrimaryRat Cardiomyocytes
| a r1 it m t t It t a |Ia rt s t rt j rt j a rt 1 | 1 isst t ia Iit r t I -1 a - sim i|a riI | t I t t r I| t m t |t t a |a r a r 1 j a I| t j | sit |t ] i-
t |1 r t t r a Ia | ra I | t a rIs a r 1 t rt 1 iIIt rt r Iia || j |a It 1 It rt m t tt
t a | rt sj t r st s t I I| t | t a rI ir t a |t ir t a rir Ira r s] t r it
Ii| rt | |a sIs. t ir 1 a t t I| t | j t rIrt j | it rt sj t r st , k r ] | | a r 1 | | t rt
m it t a r 1 ir | a m a r | t a rI Ia i|a rt , I| t st Ira r s] t r it m it t
a 1 1 t 1 It t a r1 it m t t It t a |Ia rt s a I 1 r M a r 1 1 M , rt sj t t Iitt |,
s| t a |1 | t a a st Ia | m t 1 t | It r 1 ra ] 1 ist t tt r a r 1 It r
ir st ra m -Irt t M 1 1 m t 1 ia . | t t a |Ia rt m t 1 ia t t r Ia ir ir ] t iI| t r a ] t -
i1 t r IiIir ] a 1 1 iIit r a | ] t r t s I| a I ir I|a t r t t I| t | j t rIrt -
r isI a s t | a r ] t 1 t tt r I | r It r a j t rit 1 t I I I | r. | sk a r 1 | | ! 1 t
j | it rt sj t r st . t rt j rt st r I a I ! 1 1 r ] Im | a r 1 ! 1 r ] Im |, rt sj t t Iitt |, t tt r I| t
t r Iirt I I | r t a |Ia rir ] j t rit 1 . t a r a |tt t IIt t Is t I I| t st a ] t r Is t r
K | -k 1 a t IitiI, a r K | -k -1 t j t r 1 t r I rt j t rIt r a s Ira r sIt t It 1 ir It Experimental Procedures
t a r1 it m t t It s | | a
I
j | t sj | a It Ira r sIt t Iit r ir M 1 1 st ra m -
Irt t m t 1 ia . | a r1 it m t t It s t rt I| t r t a |Ia rt 1 It r I I | r iI| I| t Two-HybridScreens
i1 t r IiIit 1 a ] t r I. | t K | -k -1 t j t r 1 t r I rt j t rIt r t t r Ia ir t 1 I| rt t K | - | t | k k \ | a iI a st 1 It r I| t t a sI I t -| | ri1 st rt t r t t r Ia ir t 1
k | ir 1 ir ] siIt s Irt m I| t IL-2 j rt m t It r t |t r t 1 a j sIrt a m t I I| t a m ir t a t i1 s 1 1 \ 1 1 Ia st 1 ir -Ira m t iI| I| t | k | \ | K k -| ir 1 ir ]
I| m i1 ir t | ir a st m ir im a | j rt m t It r a r 1 I| t luciferase] t r t ] iII Irt m 1 t m a ir . | is rt ] it r t I | k k \ t r t t m j a sst s I| t I t tir t Iir ] t r
. 1 t t . M t I| t 1 s t I j rt j a ra Iit r It r t t ||a |a r t t Ira t Is a r 1 |a t iIt ra st 1 t m a ir s a r 1 a s t r t t 1 t 1 iI| ir a | sI| -K si| Ira ] m t r I, | it | a s
a ssa s | a tt | t t r 1 t st ri| t 1 M t || t r Iir t I a |. , 1 1 \ . t |t r t 1 ir It a | sI | siIt ir I| t pAS t a sI t t j rt ssit r tt t It r. j k -
| k k \ a s t t Ira r sIt rm t 1 ir It t a sI iI| a r t m | rt r it 1 . ! m t a st
t | K k |i| ra r I| a I t t r Ia ir t 1 I| t | k | \ a t Iita Iit r 1 t m a ir Ia st 1 It Gel MobilityShift Assays andMutagenesis
t i1 t r IiI j t It r Iia | K | -k | ir 1 ir ] siIt s iI| ir I| t BNP j rt m t It r, ra r 1 t m t | K k s. | rt m t tt r ! m i||it r j rim a r t t |t r it s st rt t r t 1 ,
a j j rt t im a It | 1 1 j t siIitt t t |t r it s t rt i1 t r IiIit 1 . | rt m t a t | ir 1 i- ] t | m t | i|iI s| iII a ssa s t rt j t rIt rm t 1 iI| 1 t a | |t -sIra r 1 t 1 t |i-
] t r a t |t t Ii1 t s t t rrt sj t r 1 ir ] It j a Ia Iitt siIt s |t t a It 1 a I 1 I I , ti1 a a | t t |t r , I| t a t Iita Iir ] j |a sm i1 a s rt st a t 1 a r 1 I| t t | K k
ir st rI a s st | a t r t t 1 . | |t r t s t t r Ia ir ir ] t | K k ir st rIs ir I| t a r Ii- 1 I I , a r 1 I I , rt |a Iitt It I| t Ira r st rij Iit r sIa rI siIt 1 a ] a t I a |. ,
1 1 ! , t r I| t t t r st r sa s siIt Irt m I| t IL-2 j rt m t It r. t | a t r t t s t I st r st t rit r Ia Iit r t r t a I-t I-Ira m t t rt 1 ist a r1 t 1 . | t rt m a ir ir ]
| t ||
I I t
j rt | t s t rt a s It ||t s. | K | -1 I I . ! -| k | | | | | k | Acknowledgments
| | -1 , | K | -1I I. ! - | | | | | | | | k| | kk| | | -1 , | K | -II .
! -| | | | k | | k k k k k | | | | k | | | -1 , | | -I . ! - k | k | | k k k k | is t r| a s sa j j t rIt 1 | ] ra r Is Irt m K | 1 It | . K . 1 . a r 1 Irt m
I| t k m t rit a r 1 t a rI k sst t ia Iit r It . | . | . ! . | . M . a s sa j j t rIt 1 k k | k | -1 . | t r ] t | m t | i|iI s| iII a ssa s a Ii|itir ] I| t K | -k 1
| t | | t m t |t ] 1 t m a ir , I | t I a t t a j |t 1 ir tiIrt Ira r st rij Iit r -Ira r s|a - | a r K | 1 j t sI1 t t It ra | It ||t s| ij a I | t a I| t sIt rr . wt a rt
] ra It Ia | It I| t It ||t ir ] ir 1 iti1 a a |s It r rt a ] t r Is. . 1 t t , Y. 1 ] a a , Iit r rt a t Iit r K | iI, | rt m t ] a , M a 1 ist r , w| a s ir t a | a It 1 iI|
I| t ir 1 it a It 1 t |i] t r a t |t t Ii1 t j rt | t \ 1 , 1 1 1 t j m t I a
1 I
| -|a | t |t 1 . 1 | t t It , a r 1 K . | it t . wt a |st I| a r | | | a a r t| t r wa a r 1 | ria r
M t rt t r It r ] t r t ra Iir ] Ira r s] t r it m it t , k . itt r t r It r a ssisIa r t t j rt | t j t r rt a t Iit r ir I| t j rt st r t t t I ] t I j t | 1 | -1 | It r I 1 m ir
a I rt t m It m j t ra Ia rt , It ||t t 1 | r t r 1 t r a Ia rir ] t |t t Irt j | t rt sis. iI| ] ra j | it s, | t | t rI wt | | It r | isIt |t ] , a r 1 t a r t t ||t a ] a t s ir I| t
1 |st r |a | It r a 1 tit t a r 1 t r t t a ra ] t m t r I. | r |a | t |t 1 t t m j t IiIt r t |i] t r a t |t t Ii1 t s t rt a 1 1 t 1 a I a 1 1 -It |1
m t |a r t t t t ss, a r 1 I | t I K | -k 1 -sj t t iIit a r Iist ra m | iII Irt m K .
| it t , | a | | t I a |. , 1 1 I a s a 1 1 t 1 It r I| t sa j t rs| iII t t j t rim t r Is. | t t t itt 1 | t | ra a r I 1 , 1 1 , rt tist 1 M a rt | 1 , 1 1 .
| t ] t | m t | i|iI s| iII | a IIt rs a r 1 t |t t Irt j | t rt sis t t r 1 iIit r s a rt
1 t st ri| t 1 t |st | t rt M t || t r Iir t I a |. , 1 1 \ . iIt -1 irt t It 1 m a Ia -
References
Iit r s t rt ir Irt 1 a t t 1 ir It I| t 1 1 | j BNP j rt m t It r 1 ] a a t I
a |. , 1 1 ! | rt ||ir ] -t irt |t j t |m t ra st t | a ir rt a t Iit r a s 1 t st ri| t 1
| t Iir t ||i, | . , | t tit ||t , | . k . , | t 1 t t 1 , | . . , | t ||t ] rir t , M . k . , M a rt r ,
M t || t r Iir t I a |. , 1 1 \ .
| . ! . , j iriIt , | . , wa I| ir s, 1 . , a r 1 | t ] ] ia r i, | . 1 1 I . k m a Ia r I
Irt j t m t sir I| a I t a a st s | j t rIrt j | it t a r1 it m t j a I| is t t j rt sst 1
ir titt a r 1 a sst t ia It 1 iI| a r ir t rt a st 1 t a |t ia m st r siIitiI. | irt .
Immunocytochemistry
| t s. 82, 1 t ! .
t tisa a |itt sa rt t m t rit t r] a r ita Iit r ir j rim a r t a r1 it m t t It s,
| a sIa m a r It , ! . 1 . , | a | r a 1 ir , k . , a r 1 a t | s, | . 1 1 . Irt It | -a t Ii-
a r Ii--a t Iir ir m t a st m t r t t |t r a | a r Ii| t 1 a s a st 1 i] m a . | t ||s
ta It 1 t | a r r t |s ir | t a rI t t ||s. rt |t ta r t t It t a r1 ia t | j t rIrt j | . ! .
t rt a s| t 1 ir | | , Iit t 1 ir 1 . I X j a ra It rm a |1 t | 1 t It r ! m ir ,
| a r1 it ta st . | | a rm a t t |. 17, 1 1 .
a s| t 1 I| rt t Iim t s iI| | | , a r 1 I| t r j rt | |t t | t 1 ir | | t t r -
| | it r , | . | . , l | a , 1 . , | r t |It r , | . | . , M i||t r-1 a r t t , w. , ta r | i|st r ,
Ia ir ir ] I X | t rst st ra m , I X | k , a r 1 1 . X K | \ 1 It r 1 1 m ir . k r Ii-
M . , 1 | rt ir , . X. , a r 1 | ta r s, . M . 1 1 1 . ra r st rij Iit r a | rt ] a |a Iit r
-a t Iir ir a r Ii| t 1 a s a 1 1 t 1 a I a 1 i|a Iit r t I . 1 1 ir Irt s| j rt | |t t |
1 a rir ] t a r1 ia t ] rt I| a r 1 1 t tt |t j m t r I. k r r a . | t t. | | sit |. 55,
st |a Iit r a r 1 ir t a | a It 1 It r a r a 1 1 iIit r a | 1 1 m ir . k |It rr a Iitt |, t t ||s
I I 1 ! .
t rt ir t a | a It 1 iI| a r Ii-K | -k 1 j t |t |t r a | a r Iist ra m a I a 1 i|a Iit r
t I . \ 1 1 | a | | t I a |. , 1 1 I . a | st | a t r I|, t t ||s t rt a s| t 1 I| rt t | t |m t Ist | , | . | . , | t is, | . . , | t t 1 r t , | . | . , a r 1 1 t a |, ! . | . 1 1 I .
Iim t s ir | | iI| 1 . X K | \ 1 . k r Ii-m t a st | | | -t t r }a ] a It 1 st t - | iIIt rt r Iia | a t Iita Iit r t I Ira r st rij Iit r Ia t It rs ir 1 a t t 1 | | a
I
rt -
t r 1 a r a r Ii| t 1 a s I| t r a 1 1 t 1 a I a 1 i|a Iit r t I . \ 1 1 It r 1 1 m ir sj t r st a m j |iIa 1 t a r 1 1 a ra Iit r . K a Ia rt 386, ! ! ! .
ir j rt | |t t | st |a Iit r , a r 1 I| t t t ||s t rt a ] a ir a s| t 1 I| rt t Iim t s ir
| m m t |, | . k . , Vt r t i}, | . | . , | a ra r 1 , | . | . , 1 i] ] ir s, | . M . , | a t , | . , a r 1
| | t t r Ia ir ir ] 1 . X K | \ 1 . K a t |t a r sIa ir ir ] It r | K k a s j t rIt rm t 1
| ra | Irt t , | . | . 1 1 . | t |t sj t rir k sj t t iIit a || ir | i| iIs Ia r t Iit r t I
iI| 1 . ! ] Im | t I | is-| t r tim i1 t ir | | It r ! m ir It ||t t 1 | I| rt t
r a t |t a r j rt It ir s ir tt |tt 1 ir t t || a t Iita Iit r . t it r t t 246, t I
rir st s iI| | | .
t I 1 .
| ta r s, . 1 1 I . | t ] a |a Iit r t I t a r1 ia t ] t r t t t j rt ssit r | | k k \ I
! It . rt r 1 s | a r1 it ta st . M t 1 . 7, I ! 1 .
Transgenic Mice
| |a r a ] a r , w. M . , | t rI| t s, | . , | ra m , | . ! . , a r 1 | ra | Irt t , | . | . 1 1 . ra r s] t r it m it t t t j rt ssir ] t a |t ir t a rir a r 1 K | -k 1 ir I| t | t a rI
K a t |t a r a sst t ia Iit r t I a -t t || Ira r st rij Iit r Ia t It r | |t t | t 1 | | | - t rt t rt a It 1 a s It ||t s. k t | K k t r t t 1 ir ] a t t r sIiIa Iitt | a t Iitt
! 1 t a r 1 t t |t sj t rir k . K a Ia rt 352, 1 1 1 I . It rm t I I| t t a |t ir t a rir k t a Ia |Iit sa | a r iI 1 | t t It t I a |. , 1 1 I a s
t |t r t 1 | | | | iI| a ! a || |ir | t r a r 1 1 1 ir 1 | | | |ir | t r ir It a r | t rt t , . , | t m | t , | . M . , k tra t | , ! . k . , | t r tt r Irt , ! . V. , a r 1 | ria | is,
t t j rt ssit r tt t It r t t r Ia ir ir ] I| t -MHC j rt m t It r. | t t t j rt ssit r ! . M . 1 1 t . Irt ss-a t Iita It 1 j rt It ir | ir a st s ir t a r1 it ta st a |a r 1 is-
j a IIt rr a r 1 t | a ra t It risIit s t I I| is t t j rt ssit r tt t It r | a tt | t t r t a st . | irt . | t s. 78, 1 \ I 1 ! 1 .
1 t st ri| t 1 ! t r t s t I a |. , 1 1 \ . t ] t r t ra It Ira r s] t r it m it t t t j rt ss-
| rt j ir , | . , | a ] r ir t , | . | . , | t | iIa i||t , | . , 1 a | t rsIrt | , | . | . , k r Ia | |,
ir ] a t t r sIiIa Iitt | r a t |t a r It rm t I I| t K | -k 1 j rt It ir ir I| t | t a rI,
. , a r 1 K t m t r, M . 1 1 \ . k | t rm t r t -t r t t 1 ir ] ] t r t i1 t r IiIit s a
| | | j rim t rs t rt ] t r t ra It 1 It a ||t sj t t iIit a m j |iIit a Iit r t I a
j a I| a It r t a r1 ia t | a I r t I s| t |t Ia | m a st |t ] t r t Ira r st rij Iit r . M t |.
rt ] it r t I st | a t r t t t r t t 1 ir ] a m ir t a t i1 s 1 I 1 1 I t I I| t | a m a r
| t ||. | it |. 14, 1 ! 1 I 1 .
K | -k 1 j rt It ir , rt It rrt 1 It a s K | -k 1 1 I . X| t | |ir | t rs t r I| t t r 1 s
| ra tt r, | . | . , | t M a t , | . , | t |1 sIt ir , M . k . , a r 1 M t a r s, k . | . 1 1 1 .
t I I| t st j rim t rs a ||t t 1 t |t r ir ] ir It I| t a || siIt t I I| t -MHC
a r] t It 1 1 t tt |t j m t r Ia | t tt rt t j rt ssit r t I t a |m t 1 a |ir ir 1 a t t s j rt -
t t j rt ssit r tt t It r. | t I| I| t calcineurin a r 1 NF-AT3317--MHC
|iIt ra Iitt a r 1 | j t rIrt j | it ] rt I| t I t a r1 it m t t It s ir Ira r s] t r it
tt t It rs t rt 1 i] t sIt 1 iI| K t I| , a r 1 I| t -MHC-Ia sit r t | K k Ira ] -
m it t . | r 1 t t rir t |t ] . 133, 1 I t 1 .
m t r I a s j a riIit 1 a r 1 t |a It 1 ir t t t It ir }t t Iit r | a IIt r ! m M ris-
1 a st ] a a , | . , | t t , . ! . , ! t | t , . M . , M a r| | a m , | . | . , a r 1 | iIsis, | . K .
1 | | j 1 I . \ a r 1 1 . I m M | | k . | K k a s I| t r ir }t t It 1 ir It It rIi|itt 1
1 1 I . | is-a t Iir ] st | a t r t t s I| a I m t 1 ia It ir 1 a t Iit r t I I| t -m t sir
t t t It s 1 t ritt 1 Irt m | V| m it t , a r 1 t t t It s t rt Ira r sIt rrt 1 ir It
| t a t t | a ir ] t r t t t j rt ssit r 1 a rir ] |t II tt r Irit a |a r | j t rIrt j | 1 a t
I| t t ti1 a t Is t I j st a 1 t j rt ] r a r I | | | m it t .
It a t rIit t t r sIrit Iit r . | irt a |a Iit r . 96, 1 1 \ 1 1 1 ! 1 .
1 a tt rit | , k . , | t sIa r1 -! a t | |t , k . , | rt m t r, ! . , 1 t rrm a r r , | . , a r 1 i-
RNA Analysis
m t r , | . 1 1 \ . | t |t sj t rir k a r 1 Ira r sj |a r I t t rt r a r 1 ist a st a IIt r
t Ia | | K k a s t t ||t t It 1 a r 1 j a riIit 1 iI| ria tt | rt a ] t r I | | | | 1
| t a rI Ira r sj |a r Ia Iit r . Ia t Is a r 1 Iit Iit r . ra r sj |a r I | rt t . 26, I I 1
| | | a s rt t t m m t r 1 t 1 . | K k Irt m i|1 -Ij t a r 1 Ira r s] t r it | t a rIs,
I I ! .
a s t || a s Irt m t a |Ia rt 1 t a r1 it m t t It s, a s sa | }t t It 1 It 1 t I | |t I
1 t rti] , . | . , ! t | t , . M . , k t | i, 1 . , M t || t r Iir , ! . | . , | t |t , k . w. ,
| | ri1 ita Iit r a ] a ir sI a j a r t | t I t |i] t r a t |t t Ii1 t j rt | t s a s 1 t st ri| t 1
| ta m t , . , a r 1 M a r| | a m , | . | . 1 1 I . k r ] it It r sir | | Ij t a rt t t j It r
j rt tit a s| ! t r t s t I a |. , 1 1 t .
] t r t t t j rt ssit r ir I| t | t a rI. k | - a r 1 | k k -\ m t 1 ia It I| t rt -
sj t r st It j rt ssa rt t tt r|t a 1 . | rt t . K a I|. k t a 1 . t i. | k . 94, I ! \ 1
I ! \ .
Histology
1 t , . K . , | t m a s, | . ! . , im m t rm a r , | . k . , | i, X. , | ra r t | t , | . , a r 1
1 t a rIs Irt m i|1 -Ij t a r 1 Ira r s] t r it m it t t rt sa | }t t It 1 It | isIt -
| ra | Irt t , | . | . 1 1 ! . K | -k t 1 , a |m j | t i1 -sj t t iIit K | -k 1 Ia m i|
|t ] it a | a r a |sis. | r | rit I, | t a rIs t rt t t ||t t It 1 , Iit t 1 t tt rr i] | I ir
m t m | t r I| a I is t a |t ia m -rt ] a |a It 1 a r 1 t t | i| iIs 1 isIir t I | K k | ir 1 ir ]
1 X It rm a |ir | a IIt rt 1 iI| | | , 1 t | 1 ra It 1 ir t I| a r t |, Ira r sIt rrt 1
sj t t iIit iI. ! . | it |. | | t m . 270, 1 1 1 1 1 I .
It t |t r t , I| t r ir It j a ra IIir . | a ra IIir -t m | t 1 1 t 1 | t a rIs t rt st t -
Iit r t 1 a I \ m a r 1 sa | st | a t r I| sIa ir t 1 iI| | t m a It t |ir a r 1 1 t t , . , a r , Y. -| . , wi||ia m st r , | . , a r 1 Xa , X. 1 1 ! . | st |a Iit r t I
I t r t m t m | t rs t I I| t K | -k ] t r t Ia m i| a r 1 Ia r t Iit r a | t | a ra t - t t sir It r rt a Iir t | isIt |t ] it t t a m ir a Iit r t r iI| M a sst r Irit | rt m t
It r t t ||a ] t r wt t 1 s a r 1 | ||is, 1 1 \ . It rita Iit r t I I| t K | -k j rt It ir s. | m m a r iI 2, \ t \ I I .
| t ] a |a Iit r t I | a r1 ia t 1 j t rIrt j | | | a |t ir t a rir
I I I
1 t r ] t , | . , w| iIt , | . , | a r r it r, | . , k r] i| a , ! . k . , | a rr it r, | . 1 1 ! . M t || t r Iir , ! . | . , | a |ta | a |a r t a , | . , a r 1 M a r| | a m , | . | . 1 1 \ .
| k k -\ j t siIitt | rt ] a |a It s t t j rt ssit r t I I| t -t a r1 ia t m t sir 1 rt | a r1 | 1 t IIt t I t I sIrt It | t r t t r Ira t Iit r a r 1 I| t | a
I
Ira r sit r I
| t a t t | a ir ] t r t ir titt . M t |. | t ||. | it |. 14, \ 1 \ I \ 1 ! I . It rrt I tt r Irit a |a r m a st |t s 1 a rir ] | j t t ia a r 1 a t i1 t sis. k m . ! . | | s-
it |. 269, | t 1 1 | t 1 I .
M t || t r Iir , ! . | . , | |a t | , | . | . , M a rIir , ! . | . , a r 1 1 |st r , | . K . 1 1 t .
M a Ia Iit r a | a r a |sis t I I| t | K k | ir 1 ir ] , 1 im t rita Iit r , a r 1 Ira r st rij - ! t r t s, w. | . , a r t | t t, k . , a r 1 | t | | ir s, ! . 1 1 \ . M a rir t j a |m t r a r
Iit r a | a t Iita Iit r 1 t m a ir s t I M | | I | . M t |. | t || | it |. 16, I t I I I ! 1 t m t t a r1 ia m . 1 t tt |t j m t r Ia | a r a |sis t I t a r1 ia t ] t r t t t j rt ssit r .
| t t. | r . 200, I I .
K t rI| rt j , ! . | . , 1 t , . K . , | | t r , | . , | t m a s, | . ! . , im m t rm a r , | . k . ,
K t |a r , | . | . , k 1 m t r , k . , a r 1 | ra | Irt t , | . | . 1 1 \ . K | -k t t m j t - ! t r t s, w. | . , | ra j j , | . | . , | t t Ist | m a r , . , | ra j j , | . , 1 sir s| a , 1 . ,
r t r Is 1 t Iir t a Ia m i| t I Ira r st rij Iit r Ia t It rs Ia r] t It 1 ir -t t || a t Iita - 1 t t II, . | . , | t itir , | . , | a |it | , ! . , K ] , w. k . , a r 1 | t | | ir s, ! . 1 1 t .
Iit r . K a Ia rt 369, \ 1 I ! 1 I . k | |a Iit r t I I| t m a rir t m t sir | t a t t | a ir ] t r t |t a 1 s It 1 t sa ] t
t IIt t Is a r 1 Ia r t Iit r a | 1 t Iit iIs ir I| t | t a rI. ! . | |ir . | r tt sI. 98, 1 1 t 1 ] a a , Y. , | It | , 1 . , K a | a ] a a , 1 . , | ira | a m i, | . , a m a ra , K . , Yt s| i-
1 I . m a sa , . , K a ] a Ia , | . , Yt s| i1 a , K . , a r 1 K a | a t , | . 1 1 ! . | | a ra t It r-
ita Iit r t I I| t ! -I|a r | ir ] rt ] it r a r 1 t | rt m t st m a | a ssi] r m t r I t I | a ria , | . , | a rr s, | . | . , a r 1 im j st r , | . | . 1 1 \ . k r t r | a r t t r t t rt
I| t | a m a r | ra ir r a Iria rt Iit j t j Ii1 t ] t r t . ! . M t |. M t 1 . 73, \ ! I \ t 1 . t |t m t r I m t 1 ia It s sIim a |a Iit r t I I| t ra I -m t sir | t a t t | a ir j rt -
m t It r | a r -a 1 rt r t r] it a ] t r isI a r 1 a t Iita It 1 j rt It ir | ir a st | 1 | t t It , . ! . , a m a ra , ! . , | ir t a i1 , | . | . , t t t i, M . ! . , a r 1 1 K t i||,
ir | j t rIrt j | t I t a r1 ia t m t t It s. ! . | it |. | | t m . 269, 1 I I ! 1 I I .
| . k . 1 1 I . | | ! 1 t - a r 1 | sk -st r siIitt a t Iita Iit r t I I| t ir It r|t a -
| ir -I j rt m t It r | t a |t ir t a rir . K a Ia rt 357, t 1 I t 1 \ . | a r|ir t r, ! . . , | a ria , . , a r 1 im j st r , | . | . 1 1 1 . | IIt t Is t I j t rIa s-
sis It t ir t r -a ] t r isI-m t 1 ia It 1 j | t sj | a Ii1 |ir t siIi1 t Ia rr t tt r | a |m iIt r, | . k . , a r 1 t |a rt , | . ! . 1 1 I . M t |t t a |a r m t t | a r ism s rt ] a -
a r 1 m t t a r1 ia | t t || | j t rIrt j | ir r t t r a Ia | ra I m t t It s. | t j t rit r - |a Iir ] I| t m t Ii|a m t r I rt sj t r st It | a
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Iia 46, \ .
t a a sa | It r Ia m i|ia | | j t rIrt j | it t a r1 it m t j a I| . | a sit | t s. | a r1 it |.
92, t 1 I \ . | a rr s, | . | . , | a ria , | . , a r 1 im j st r , | . | . 1 1 ! . M -| k , | k r| ,
a r 1 j t |t m t r Is a rt rt | a irt 1 It r
-a 1 rt r t r] it ir 1 a t Iit r t I I| t | a r| , ! . , a | t a t | i, k . , a r 1 | a rm a , . 1 1 t . | | a ra t It rita Iit r t I a
s| t |t Ia | -a t Iir j rt m t It r 1 a rir ] t a r1 ia t m t t It | j t rIrt j | . ! . r t ist It rm t I I| t K | -k r a t |t a r Ia m i| t I a t Iita It 1 t t ||s ] t r t
| it |. | | t m . 270, \ 1 \ I .
Ia m i| m t m | t r K | -k t . ! . | it |. | | t m . 271, I 1 1 \ I 1 1 I .
| t m a rt , | . , a r 1 Ya ta | i, Y. 1 1 1 . | t r Irt | t I t a r1 ia t ] t r t t t j rt ssit r | t rrt a a |I, | . | . , | a r r t r , | . | . , | t r , Y. . , Va Ir t r, . | . , M t r] a r , ! . | .
| m t t | a r it a | sIrt ss. k r r a . | t t. | | sit |. 55, ! ! I ! . 1 1 \ . | t t iIa Iit r -t t r Ira t Iit r t t a j |ir ] ir ist |a It 1 m t t a r1 ia m Irt m
1 t ] s iI| t t m j t r sa It 1 |t II tt r Irit a |a r | j t rIrt j | . k m . ! . | | sit |. | a 1 t | , . , | t m a rt , | . , M ita r t , . , Ya m a ta | i, . , l t a , Y. , | it }im a ,
266, 1 I \ 1 t -1 I \ \ I . | . , a | t | t s| i, K . , a r 1 Ya ta | i, Y. 1 1 I . k r ] it It r sir | | sIim a |a It s
t -}a r K 1 I -It rm ir a | | ir a st ir t a |Ia rt 1 t a r1 ia t m t t It s t I r t t r a Ia | | a t , k . , | a t , | . , a r 1 1 t ] a r , | . | . 1 1 I . ra r st rij Iit r Ia t It rs t I
ra Is. | irt . | t s. 80, 1 1 \ t . I| t K | -k Ia m i|. rt ] a |a Iit r a r 1 Ia r t Iit r . k r r a . | t t. | m m a r t |. 15,
I 1 I I \ I . | t ta t it -M i|itt }t tit , | . , wt r ] , V. . 1 . , a r 1 | a r1 r t r, | . | . 1 1 t .
t |t t Iitt rt ] a |a Iit r t I I| t a Iria | r a Iria rt Iit j t j Ii1 t ] t r t | ir 1 iti1 - | t i1 , | . ! . , a r 1 Ya t t a | , M . 1 . 1 . | t It rm ir a r Is t I |t II tt r Irit a |a r
a a | t t m j t r t r Is t I I| t a t Iita It r j rt It ir - t t m j |t t . | r 1 t t rir t |t ] Ia r t Iit r t r t t a r a IIt r t a r1 ia t Ira r sj |a r Ia Iit r . | r. 1 t a rI ! . 59,
137, 1 I . 1 1 I \ 1 I .
| t | a t r r t t , ! . Y. , w| iIt , | . , | a r r it r, | . , k r] i| a , ! . k . , a r 1 | a rr it r,
| t t r t , ! . w. , 1 t 1 ] t , M . | . , M t | a IIrt , | . | . , | a t , k . , a r 1 | |im t | t r,
| . 1 1 . Irt It | -ir 1 a t t 1 ir t rt a st t I rt sIir ] ir Ira t t ||a |a r t a |t ia m | . | . 1 1 \ . k t t m m t r Ia t It r rt ] a |a It s | t I| | - a r 1 | t -sj t t iIit
t t r t t r Ira Iit r ir sir ] |t ] a ir t a -j i] tt r Irit a |a r m t t It s. | t j . | | s- t It | ir t ] t r t t t j rt ssit r . | M | 1 ! . 13, t I ! t 1 1 .
it |. 6, 1 I ! 1 I .
a 1 t s| im a , ! . , a r 1 | ta m t , . 1 1 1 . i] r a | Ira r s1 a t Iit r j a I| a s
| t iIt , M . | . , | a ] t , | . , a r 1 k m | |t r, . | . 1 1 \ . | t ] a |a Iit r t I k K |
t I a r ] it It r sir | | -ir 1 a t t 1 t -fos] t r t t t j rt ssit r ir t a r1 ia t m t t It s
st t rt Iit r | t r 1 t I| t |ir - ir t a |Ia rt 1 a Iria | m t t It s. 1 t st r siIita - ir tiIrt . | irt . | t s. 73, \ I \ \ 1 .
Iit r a r 1 rt t t j It r sa | Ij t . k m . ! . | | sit |. 267, 1 I 1 1 1 I I 1 1 .
a 1 t s| im a , ! . , a r 1 | ta m t , . 1 1 I . | t t t ||a |a r a r 1 m t |t t a |a r
| ir , | . , | t | | t ta , k . , 1 t m s| t r, | . , a r 1 t | a t m a r , | . . 1 1 t . k |- rt sj t r st t I t a r1 ia t m t t It s It m t t | a r it a | sIrt ss. k r r a . | t t.
It rt 1 t a r1 ia t Irt j t r ir ir tiIrt Ia r t Iit r ir I| t j rt st r t t t I a m a Ia - | | sit |. 59, ! ! ! I .
Iit r im j |it a It 1 ir Ia m i|ia | | j t rIrt j | it t a r1 it m t j a I| . ! . | |ir . | r -
a 1 t s| im a , ! . , Xa , Y. , |a It r, 1 . . , a r 1 | ta m t , . 1 1 1 . k a It t rir t
tt sI. 97, I \ I I \ .
rt |t a st t I a r ] it It r sir | | m t 1 ia It s sIrt It | -ir 1 a t t 1 | j t rIrt j | t I
| t | , | . , | a rt , ! . k . , | im , ! . , 1 t ] a r , | . | . , a r 1 | a t , k . 1 1 t a . -t t ||
t a r1 ia t m t t It s ir tiIrt . | t || 75, 1 I I 1 \ .
rt t t j It r sIim a |a Iit r t |it iIs a r t a r| j | a st t I a t Iita Iit r a r 1 a |a It r
a t | i, Y. , | a ri| a ra , . , 1 t r ] t , | . , a r a | a , | . 1 1 1 . t r sit r a r 1
j | a st t I 1 t a t Iita Iit r t I I| t Ira r st rij Iit r Ia t It r K | k . M t |. | t ||.
ir Ira t t ||a |a r t a |t ia m Ira r sit r I t I a t Iita It 1 It rrt I tt r Irit a |a r m a st |t
| it |. 16, 1 1 \ ! 1 1 ! \ .
ir rt sj t r st It sIt j |t r ] I| t | a r ] t s. k 1 t. | t j . M t 1 . | it |. 332,
| t | , | . , | a , | . . Y. , | a rt , ! . , Vit |a , ! . | . | . , | t a , | . , | t rrir t ,
t 1 1 t \ I .
| . k . , a r 1 | a t , k . 1 1 t | . | a |t ir t a rir | ir 1 s I| t Ira r st rij Iit r Ia t It r
t | ir ] t r, | . 1 . , | t | m , M . , t | m i1 I, | . , | a rt tt s| i, | . , | t tt r 1 it | ,
K | k a r 1 rt tt rsi| | rt ] a |a It s iIs a t IitiI. ! . | it |. | | t m . 271,
| . , | |t st | , M . , | ra a st , | . | . , a r 1 | r1 m a r r , | . 1 1 ! . | r t | a r ] t 1
1 \ 1 1 .
j rt It ir |t tt |s t I | | | k | | a r 1 j | t sj | t |a m | a r | a I rt 1 a t t 1 | a
I
-
| a | | , | . , | | t s| , | . , a r 1 | it t , K . | . 1 1 I . | t j rt ssit r t I K | -k -
k | a st a t IitiI t I t a r1 ia t sa rt t j |a sm it rt Iit a |a m Irt m 1 i|a It 1
Ia m i| j rt It ir s ir r t rm a | | a m a r t t ||s. M t |. | t ||. | it |. 17, I \ I ! t a r1 it m t j a I| j a Iit r Is t t m j a rt 1 iI| j a Iit r Is iI| r t r Ia i|ir ]
I \ I . | t a rIs. | irt a |a Iit r 92, 1 I I 1 1 I I .
M a r| a r , | . , | iIa | a tt , M . , | a sa t | a , 1 . , | t rIt rIit |1 , ! . | . , Ya t , | . . , | a , | . . Y. , 1 t , k . M . , | a ] | a ta r , k . , | im , ! . , ! ia r , ! . , | a r| , ! . ,
a r 1 | | a t | t , V. | . 1 I . | r Ira t t ||a |a r Irt t t a |t ia m t t r t t r Ira Iit r s | a rm a , . , | a t , k . , a r 1 1 t ] a r , | . | . 1 1 ! . | m m a r t sa j j rt ssitt
m t a sa rt 1 iI| 1 | K M | sj t t Irt st t j ir ir Ia t I It rrt I | t a rIs. | rt t . 1 ra ] s j rt tt r I a ra j i1 1 t j | t sj | t r|a Iit r t I Ira r st rij Iit r Ia t It r
K a I|. k t a 1 . t i. | k . 84, t 1 1 ! t 1 1 1 K | k ir sIim a |a It 1 im m a r t t t ||s. | rt t . K a I|. k t a 1 . t i. | k 92,
I 1 ! I 1 1 . M a sa 1 a , | . . , K a iIt , Y. , t | a m iIsa , 1 . , | a m j | t ||, | . , a iIt , | . , 1 a r -
r a m , | . , k ra i, | . -| . , a r 1 k ra i, K . 1 1 ! . K | -k t , a r t tt | m t m | t r It m m t r, | . M . , a r 1 | |t t , | . | . 1 1 \ . | a a | t a |t ia m it r rt ] a |a Iit r
t I I| t r a t |t a r Ia t It r t I a t Iita It 1 t t ||s Ia m i| I| a I is t t j rt sst 1 t I t a |t ir t a rir | t a |m t 1 a |ir a r 1 t a |t ir t a rir | . | it t | t m isIr 33,
j rt 1 t m ir a r I| ir I| t I| m a s. M t |. | t ||. | it |. 15, I t 1 I I I 1 t . t ! 1 t t t .
M t | a IIrt , | . | . , | a t , | . , | t rj j t |a , . | . , ! a ir , ! . , | a 1 a |ia r , . M . , a , . , l | a t , M . , wt | t r, | . , | a ] sIt r, 1 . | . , a r 1 | IIt |, | . 1 1 ! .
1 t , k . M . , | a r] t t r , | . , | a r t , w. . , | a m | t rI, ! . K . , | a rra r , . , t I | isIri| a Iit r a r 1 a t IitiI t I t a |t ir t a rir ir ra I Iissa t s. | ti1 t r t t It r
a |. 1 1 1 . | st |a Iit r t I I| t t t |t sj t rir -st r siIitt t t || Ira r st rij Iit r j t sI-Ira r st rij Iit r a | rt ] a |a Iit r t I It sIis-sj t t iIit t a |t ir t a rir | . | a r.
Ia t It r K | -k j . t it r t t 262, I ! 1 I ! \ . ! . | it t | t m . 230, \ t 1 \ I \ .
M t || t r Iir , ! . | . , a r 1 1 |st r , | . K . 1 1 I . | k k \ . a r t tt | Ira r st rij - | t r| a rr , k . , | t r| a rr , ! . , | | t r , . -| . , | t t rs, . , | a | t iIa , 1 . | . ,
| t ra m ist t , ! . | . , a r 1 | | it r , | . | . 1 1 1 . 1 | a s-1 t j t r 1 t r I j a I| a s Iit r a | rt ] a |a It r t I t a r1 ia t | j t rIrt j | ! | irt a |a Iit r 96, 1 1 1 1 1 ! .
| t ||
I I
t a r a t Iita It m t rj | t |t ] it a | a r 1 ] t r t Iit m a r| t rs t I t a r1 ia t m a st |t
t t || | j t rIrt j | . ! . | it |. | | t m . 268, I I \ \ I I \ 1 .
Vi| sIrt m , | . | . , a r 1 | t ir a r 1 , | . k . 1 1 t . | t r Ira t Ii|t j rt It ir m a Ia -
Iit r s a r 1 | t a rI 1 ist a st . | a rr. 1 j ir . | t || | it |. 8, 1 I 1 ! .
wa I| ir s, 1 . , t i1 m a r , ! . | . , a r 1 t i1 m a r , | . | . 1 1 ! . | a m i|ia | | j t r-
Irt j | it t a r1 it m t j a I| . a ] t r t Iit m t 1 t | t I t a r1 ia t | j t rIrt j | .
1 a m . M t |. | t r t I. 4, I I I I I .
wt |It , . k . , l | t a , | . , | t Ist | , V. , | | t r , | . , Yt a , k . , 1 t , . K . ,
| ra | Irt t , | . | . , wa ] r t r, | . , a r 1 Vt r1 ir t , | . | . 1 1 I . | r a sa a | | t |-
|i| t a rt | iIt t Ia rt ir I| t | K k -| ir 1 ir ] 1 t m a ir t I I| t Ira r st rij Iit r
Ia t It r K | k t . K a Ia rt 385, I I I t .
wt t 1 s, k . | . , a r 1 | ||is, | . | . 1 1 \ . | a | t ra It r 1 isIt j a I| t |t ] . k
| t m j |t It | t It rt r t t . K t Yt r| . | | a rt | i|| | itir ] sIt r t | a | |is| t rs ,
j j . I . 1 .
Ya m a ta | i, . , | t m a rt , | . , | a 1 t | , . , l t a , Y. , | it }im a , | . , 1 irt , Y. ,
M ita r t , . , M a t m a ra , | . , | a ri| a ra , 1 . , k i| a a , | . , a | a r t , 1 . , a r 1
Ya ta | i, Y. 1 1 t . | r 1 t I| t |ir - is ir tt |tt 1 ir m t t | a r it a | sIrt ss-
ir 1 a t t 1 t a r1 it m t t It | j t rIrt j | . ! . | it |. | | t m . 271, 1 I I 1 I I .
Ya m a ta | i, . , | t m a rt , | . , l t a , Y. , | a 1 t | , . , | it }im a , | . , 1 irt i, Y. ,
M ita r t , . , k i| a a , | . , a | a r t , 1 . , a r 1 Ya ta | i, Y. 1 1 I . K t rt j i-
r t j | rir t ir 1 a t t s I| t ra I- | ir a st Im iIt ] t r -a t Iita It 1 j rt It ir | ir a st
t a st a 1 t I| rt a ] | | t I| - a r 1 -a 1 rt r t t t j It rs. | irt a |a Iit r 95,
I t 1 I t .
l t a , Y. , | t m a rt , | . , Ya m a ta | i, . , k i| a a , | . , | a 1 t | , . , | it }im a ,
| . , 1 irt i, Y. , M ita r t , . , a r 1 Ya ta | i, Y. 1 1 t . | rt It ir | ir a st | ,
| a I r t I Irt sir t | ir a st s t r ra s, j |a s a t riIit a | rt |t ir a r ] it It r sir
| | ir 1 a t t 1 a t Iita Iit r t I | a I- | ir a st a r 1 t t Ira t t ||a |a r si] r a |-rt ] a -
|a It 1 j rt It ir | ir a st s ir t a r1 ia t m t t It s. ! . | it |. | | t m . 271, 1 1 ! 1 I
1 1 ! 1 I .