| First Author | Taniike M | Year | 2008 |
| Journal | Circulation | Volume | 117 |
| Issue | 4 | Pages | 545-52 |
| PubMed ID | 18195174 | Mgi Jnum | J:145085 |
| Mgi Id | MGI:3833490 | Doi | 10.1161/CIRCULATIONAHA.107.710434 |
| Citation | Taniike M, et al. (2008) Apoptosis signal-regulating kinase 1/p38 signaling pathway negatively regulates physiological hypertrophy. Circulation 117(4):545-52 |
| abstractText | 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. |
