title: p38 Mitogen-activated protein kinase mediates a negative inotropic effect in cardiac myocytes.
abstract: 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-beta-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 Ca(2+) currents or Ca(2+)(i) transients. MKK3bE-induced p38 activation had no significant effect on pH(i), whereas SB203580 had a minor effect to elevate pH(i). 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 Ca(2+), rather than by altering Ca(2+)(i) homeostasis and that the reduced myofilament Ca(2+) sensitivity is unlikely attributable to troponin I phosphorylation or alterations in pH(i). 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.
authors.affiliation: Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21224, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Liao
authors.forename: Shi-Qiang
authors.initials: SQ
authors.lastname: Wang
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Meizi
authors.initials: M
authors.lastname: Zheng
authors.forename: Sheng-Jun
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022761:Gene Transfer, Horizontal; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D019210:Troponin I / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D019210:Troponin I; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases