Published online before print April 19, 2004, doi: 10.1161/01.CIR.0000127126.73759.23
(Circulation. 2004;109:1938-1941.)
© 2004 American Heart Association, Inc.
Brief Rapid Communications |
MEK1-ERK2 Signaling Pathway Protects Myocardium From Ischemic Injury In Vivo
From the Department of Cardiology, Maastricht University, and Heart Lung Center Utrecht, Maastricht and Utrecht, Netherlands (D.J.L., L.J.D., P.A.D.); Departments of Pediatrics (O.F.B., B.J.W., N.H.P., R.A.K., J.D.M.) and Physiology (J.N.L.), University of Cincinnati, Children’s Hospital Medical Center, Cincinnati, Ohio; Institut de recherches cliniques de Montrèal, Departments of Pharmacology and Molecular Biology, Universitè of Montrèal, Montrèal, Quebec, Canada (L.V., M.K.S., S.M.); and Department of Developmental Biology and Cancer Research, Institute of Signaling, Centre Antoine Lacassagne, Nice, France (J.P., G.P.).
Correspondence to Jeffery D. Molkentin, PhD, Division of Molecular Cardiovascular Biology, Department of Pediatrics, Children’s Hospital Medical Center, 3333 Burnet Ave MLC7020, Cincinnati, OH 45229-3039. E-mail jeff.molkentin{at}cchmc.org
Received August 22, 2003; de novo received December 22, 2003; revision received March 15, 2004; accepted March 15, 2004.
Background— Myocardial infarction causes a rapid and largely irreversible loss of cardiac myocytes that can lead to sudden death, ventricular dilation, and heart failure. Members of the mitogen-activated protein kinase (MAPK) signaling cascade have been implicated as important effectors of cardiac myocyte cell death in response to diverse stimuli, including ischemia-reperfusion injury. Specifically, activation of the extracellular signal–regulated kinases 1/2 (ERK1/2) has been associated with cardioprotection, likely through antagonism of apoptotic regulatory pathways.
Methods and Results— To establish a causal relationship between ERK1/2 signaling and cardioprotection, we analyzed Erk1 nullizygous gene-targeted mice, Erk2 heterozygous gene-targeted mice, and transgenic mice with activated MEK1-ERK1/2 signaling in the heart. Although MEK1 transgenic mice were largely resistant to ischemia-reperfusion injury, Erk2+/– gene-targeted mice showed enhanced infarction areas, DNA laddering, and terminal deoxynucleotidyl transferase–mediated dUTP biotin nick-end labeling (TUNEL) compared with littermate controls. In contrast, enhanced MEK1-ERK1/2 signaling protected hearts from DNA laddering, TUNEL, and preserved hemodynamic function assessed by pressure-volume loop recordings after ischemia-reperfusion injury.
Conclusions— These data are the first to demonstrate that ERK2 signaling is required to protect the myocardium from ischemia-reperfusion injury in vivo.
Key Words: ischemia • cardiac output • mitogen-activated protein kinases • infarction • signal transduction
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