Progression of heart failure was suppressed by inhibition of apoptosis signal-regulating kinase 1 via transcoronary gene transfer.
OBJECTIVE
We examined whether the inhibition of apoptosis signal-regulating kinase 1 (ASK1) would attenuate the progression of heart failure in TO-2 hamsters with hereditary dilated cardiomyopathy.


BACKGROUND
Heart failure remains the leading cause of mortality and requires novel therapies targeting the biologically relevant processes within cardiomyocytes that lead to cell death. Apoptosis signal-regulating kinase 1 is a key signaling molecule for cardiomyocyte death.


METHODS
We generated recombinant adeno-associated virus (rAAV) expressing an N-terminal truncated form of the dominant-negative mutant of ASK1 (ASKdeltaN(KR)). TO-2 hamsters were subjected to an in vivo rAAV transcoronary transfer.


RESULTS
ASKdeltaN(KR) retained its dominant-negative activity in vitro. The rAAV expressing ASKdeltaN(KR) treatment inhibited ASK1 activation in the hamster hearts and suppressed progression of ventricular remodeling such as chamber dilation, impairment of contractile and relaxation functions, and fibrosis. Inhibition of ASK1 reduced the number of apoptotic cells and selectively attenuated c-Jun NH2-terminal kinase activation. Although the deficiency of delta-sarcoglycan, a genetic defect in the hamster, leads to the degradation of dystrophin, the treatment significantly protected hearts from this degradation, probably by inhibiting calpain activation.


CONCLUSIONS
Apoptosis signal-regulating kinase 1 is involved in the pathogenesis of heart failure progression, mediated through c-Jun NH2-terminal kinase-mediated apoptosis and calpain-dependent dystrophin cleavage, and may be a therapeutic target to treat patients with heart failure.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Shungo
S
Hikoso
Yasuhiro
Y
Ikeda
Osamu
O
Yamaguchi
Toshihiro
T
Takeda
Yoshiharu
Y
Higuchi
Shinichi
S
Hirotani
Kazunori
K
Kashiwase
Michio
M
Yamada
Michio
M
Asahi
Yasushi
Y
Matsumura
Kazuhiko
K
Nishida
Masunori
M
Matsuzaki
Masatsugu
M
Hori
Kinya
K
Otsu
D000818:Animals; D006224:Cricetinae; D000229:Dependovirus; D004195:Disease Models, Animal; D018450:Disease Progression; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000201:enzymology* / Q000628:therapy*; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism; D019076:Transgenes; D016896:Treatment Outcome; D020257:Ventricular Remodeling
D048848:MAP Kinase Kinase Kinase 5