Apoptosis signal-regulating kinase 1/p38 signaling pathway negatively regulates physiological hypertrophy.

Abstract

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 p38alpha-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.

• Authors: Masayuki Taniike, Osamu Yamaguchi, Ikuko Tsujimoto, Shungo Hikoso, Toshihiro Takeda, Atsuko Nakai, Shigemiki Omiya, Isamu Mizote, Yuko Nakano, Yoshiharu Higuchi, Yasushi Matsumura, Kazuhiko Nishida, Hidenori Ichijo, Masatsugu Hori, Kinya Otsu
• Journal: Circulation (Circulation) Vol. 117 Issue 4 Pg. 545-52 (Jan 29 2008) ISSN: 1524-4539 [Electronic] United States
• PMID: 18195174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-akt
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• Map3k5 protein, mouse

Topics

• Animals
• Apoptosis
• Cardiomegaly (etiology, metabolism)
• Hypertrophy (etiology)
• MAP Kinase Kinase Kinase 5 (metabolism, physiology)
• Mice
• Mice, Knockout
• Physical Conditioning, Animal (physiology)
• Proto-Oncogene Proteins c-akt
• Rats
• Signal Transduction
• p38 Mitogen-Activated Protein Kinases (metabolism)