MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo

DJ Lips, OF Bueno, BJ Wilkins, NH Purcell, RA Kaiser… - Circulation, 2004 - Am Heart Assoc
DJ Lips, OF Bueno, BJ Wilkins, NH Purcell, RA Kaiser, JN Lorenz, L Voisin, MK Saba-El-Leil…
Circulation, 2004Am Heart Assoc
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 …
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.
Am Heart Assoc