Circulation Research. 2002;90:190-196
Published online before print December 27, 2001, doi: 10.1161/hh0202.104220
Published online before print December 27, 2001, doi: 10.1161/hh0202.104220
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© 2002 American Heart Association, Inc.
Cellular Biology |
p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes
From the Department of Physiology (P.L., Meizi Zheng, Y.W.), School of Medicine, University of Maryland, Baltimore, Md; Laboratory of Cardiovascular Science (S.-Q.W., S.W., Ming Zheng, S.-J.Z., H.C.. R.-P.X.), Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Md; and Health Science Center (Ming Zheng), College of Life Science (H.C.), Peking University, Beijing, China.
Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail XiaoR{at}grc.nia.nih.gov; and Yibin Wang, PhD, Department of Physiology, School of Medicine, University of Maryland, 660 W Redwood, Howard Hall 510, Baltimore, MD 21201. E-mail wang001@umaryland.edu
p38 Mitogen-activated protein kinase (MAPK) is one of the most ancient signaling molecules and is involved in multiple cellular processes, including cell proliferation, cell growth, and cell death. In the heart, enhanced activation of p38 MAPK is associated with ischemia/reperfusion injury and the onset of heart failure. In the present study, we investigated the function of p38 MAPK in regulating cardiac contractility and its underlying mechanisms. In cultured adult rat cardiomyocytes, activation of p38 MAPK by adenoviral gene transfer of an activated mutant of its upstream kinase, MKK3bE, led to a significant reduction in baseline contractility, compared with uninfected cells or those infected with a control adenoviral vector (Adv-ß-galactosidase). The inhibitory effect of MKK3bE on contractility was largely prevented by coexpressing a dominant-negative mutant of p38 MAPK or treating cells with a p38 MAPK inhibitor, SB203580. Conversely, inhibition of endogenous p38 MAPK activity by SB203580 rapidly and reversibly enhanced cell contractility in a dose-dependent manner, without altering L-type Ca2+ currents or Ca2+i transients. MKK3bE-induced p38 activation had no significant effect on pHi, whereas SB203580 had a minor effect to elevate pHi. Furthermore, activation of p38 MAPK was unable to increase troponin I phosphorylation. Thus, we conclude that the negative inotropic effect of p38 MAPK is mediated by decreasing myofilament response to Ca2+, rather than by altering Ca2+i homeostasis and that the reduced myofilament Ca2+ sensitivity is unlikely attributable to troponin I phosphorylation or alterations in pHi. These findings reveal a novel function of p38 MAPK and shed a new light on our understanding of the coincidence of p38 MAPK activation and the onset of heart failure.
Key Words: p38 mitogen-activated protein kinase • cardiac contractility • excitation-contraction coupling • troponin I • intracellular pH
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