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p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes

Liao, Pu ; Wang, Shi-Qiang ; Wang, Su ; Zheng, Ming ; Zheng, Meizi ; Zhang, Sheng-Jun ; Cheng, Heping ; Wang, Yibin ; Xiao, Rui-Ping

Circulation research, 2002-02, Vol.90 (2), p.190-196 [Periódico revisado por pares]

Hagerstown, MD: American Heart Association, Inc

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Título:
p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes
Autor: Liao, Pu ; Wang, Shi-Qiang ; Wang, Su ; Zheng, Ming ; Zheng, Meizi ; Zhang, Sheng-Jun ; Cheng, Heping ; Wang, Yibin ; Xiao, Rui-Ping
Assuntos: Actin Cytoskeleton - metabolism ; Adenoviridae - genetics ; Animals ; Biological and medical sciences ; Calcium Channels, L-Type - metabolism ; Calcium Signaling - drug effects ; Calcium Signaling - physiology ; Cells, Cultured ; Enzyme Activation - drug effects ; Enzyme Activation - physiology ; Enzyme Inhibitors - pharmacology ; Fundamental and applied biological sciences. Psychology ; Gene Transfer, Horizontal ; Genetic Vectors - genetics ; Genetic Vectors - metabolism ; Heart ; Hydrogen-Ion Concentration ; Intracellular Fluid - metabolism ; Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Mitogen-Activated Protein Kinases - genetics ; Mitogen-Activated Protein Kinases - metabolism ; Mutagenesis, Site-Directed ; Myocardial Contraction - drug effects ; Myocardial Contraction - physiology ; Myocardium - cytology ; Myocardium - enzymology ; p38 Mitogen-Activated Protein Kinases ; Patch-Clamp Techniques ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction - physiology ; Troponin I - genetics ; Troponin I - metabolism ; Vertebrates: cardiovascular system
É parte de: Circulation research, 2002-02, Vol.90 (2), p.190-196
Notas: Both authors contributed equally to this study.
Descrição: 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-β-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 currents or Cai 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 Ca, rather than by altering Cai homeostasis and that the reduced myofilament Ca 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.
Editor: Hagerstown, MD: American Heart Association, Inc
Idioma: Inglês

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p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes

Liao, Pu ; Wang, Shi-Qiang ; Wang, Su ; Zheng, Ming ; Zheng, Meizi ; Zhang, Sheng-Jun ; Cheng, Heping ; Wang, Yibin ; Xiao, Rui-Ping

Hagerstown, MD: American Heart Association, Inc

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