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PRECLINICAL STUDY

Progression of Heart Failure Was Suppressed by Inhibition of Apoptosis Signal-Regulating Kinase 1 Via Transcoronary Gene Transfer

Shungo Hikoso, MD, PhD^_*,1,2, Yasuhiro Ikeda, MD, PhD^,2, Osamu Yamaguchi, MD, PhD^_*,1, Toshihiro Takeda, MD, PhD^_*, Yoshiharu Higuchi, MD, PhD^_*, Shinichi Hirotani, MD, PhD^_*, Kazunori Kashiwase, MD, PhD^_*, Michio Yamada, MD, Michio Asahi, MD, PhD, Yasushi Matsumura, MD, PhD, Kazuhiko Nishida, MD, PhD^_*, Masunori Matsuzaki, MD, PhD, FACC^,||, Masatsugu Hori, MD, PhD, FACC^_* and Kinya Otsu, MD, PhD^_*,_*

^_* Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan
Department of Biochemistry, Osaka University Graduate School of Medicine, Suita, Japan
Department of Medical Information Science, Osaka University Graduate School of Medicine, Suita, Japan
Department of Molecular Cardiovascular Biology, Yamaguchi University Graduate School of Medicine, Ube, Japan
^|| Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.

Manuscript received October 24, 2006; revised manuscript received February 28, 2007, accepted March 20, 2007.

^_* Reprint requests and correspondence: Dr. Kinya Otsu, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. (Email: kotsu{at}medone.med.osaka-u.ac.jp).

Objectives: 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 (ASKN(KR)). TO-2 hamsters were subjected to an in vivo rAAV transcoronary transfer.

Results: ASKN(KR) retained its dominant-negative activity in vitro. The rAAV expressing ASKN(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 -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.

Abbreviations and Acronyms   ANOVA = analysis of variance   ASK1 = apoptosis signal-regulating kinase 1   ERK = extracellular signal-regulated kinase   JNK = c-Jun NH2-terminal kinase   LV = left ventricular   LVPWT = left ventricular posterior wall   MAP = mitogen-activated protein   MKK = mitogen-activated protein kinase kinase   rAAV = recombinant adeno-associated virus   TUNEL = terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling

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