Published Online
on January 14, 2008

A more recent version of this article appeared on January 29, 2008

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Submitted on April 19, 2007
Accepted on November 2, 2007

Apoptosis Signal-Regulating Kinase 1/p38 Signaling Pathway Negatively Regulates Physiological Hypertrophy

Masayuki Taniike MD, Osamu Yamaguchi MD, PhD, Ikuko Tsujimoto DDS, PhD, Shungo Hikoso MD, PhD, Toshihiro Takeda MD, PhD, Atsuko Nakai MS, Shigemiki Omiya MD, Isamu Mizote MD, Yuko Nakano DDS, Yoshiharu Higuchi MD, PhD, Yasushi Matsumura MD, PhD, Kazuhiko Nishida MD, PhD, Hidenori Ichijo PhD, Masatsugu Hori MD, PhD, and Kinya Otsu MD, PhD^*

From the Departments of Cardiovascular Medicine (M.T., O.Y., S.H., T.T., A.N., S.O., I.M., Y.H., K.N., M.H., K.O.), and Medical Information Science (Y.M.), Graduate School of Medicine and First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry (I.T., Y.N.), Osaka University, Osaka; and Laboratory of Cell Signaling, Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo (H.I.), Japan.
From the Departments of Cardiovascular Medicine (M.T., O.Y., S.H., T.T., A.N., S.O., I.M., Y.H., K.N., M.H., K.O.) and Medical Information Science (Y.M.), Graduate School of Medicine and First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry (I.T., Y.N.), Osaka University, Osaka; and Laboratory of Cell Signaling, Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo (H.I.), Japan.

^* To whom correspondence should be addressed. E-mail: kotsu{at}medone.med.osaka-u.ac.jp.

Background—Mechanical stress on the heart can lead to crucially different outcomes. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy, characterized by a normal cardiac structure and normal or enhanced cardiac function. Pathological stimuli such as hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Apoptosis signal-regulating kinase 1 (ASK1) is known to be involved in pathological cardiac remodeling, but it has not been determined whether ASK1 pathways coordinate the signaling cascade leading to physiological type cardiac growth.

Methods and Results—To evaluate the role of ASK1 in the physiological form of cardiac growth, mice lacking ASK1 (ASK1^-/-) were exercised by swimming for 4 weeks. ASK1^-/- mice showed exaggerated growth of the heart accompanied by typical characteristics of physiological hypertrophy. Their swimming-induced activation of Akt, a key molecule in the signaling cascade of physiological hypertrophy, increased more than that seen in wild-type controls. The activation of p38, a downstream kinase of ASK1, was suppressed selectively in the swimming-exercised ASK1^-/- mice. Furthermore, the inhibition of ASK1 or p38 activity enhanced insulin-like growth factor 1–induced protein synthesis in rat neonatal ventricular cardiomyocytes, and the treatment with a specific inhibitor of p38 resulted in enhancement of Akt activation and suppression of protein phosphatase 2A activation. The cardiac-specific p38-deficient mice developed an exacerbated form of cardiac hypertrophy in response to swimming exercise.

Conclusions—These results indicate that the ASK1/p38 signaling pathway negatively regulates physiological hypertrophy.

Key words: exercise • hypertrophy • signal transduction

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