(Circulation. 2001;104:325.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
JAK/STAT Signaling Is Associated With Cardiac Dysfunction During Ischemia and Reperfusion
From the Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Health Science Center Brooklyn, Brooklyn, NY (E.M., M.E., Y.G., M.A.Q.S.), and the Department of Surgery and Physiology, University of Connecticut School of Medicine, Farmington (N.M., M.S., D.K.D.).
Correspondence to M.A.Q. Siddiqui, PhD, Department of Anatomy and Cell Biology, State University of New York Health Science Center at Brooklyn, 450 Clarkson Ave, Brooklyn, NY 11203. E-mail msiddiqui{at}netmail.hscbklyn.edu
Background— Activation of the heart renin-angiotensin system (RAS) under pathophysiological conditions has been correlated with the development of ischemic injury. The binding of angiotensin II to its receptors triggers induction of several, perhaps multifunctional, intracellular signaling pathways, notable among them the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In this study, we investigated whether the JAK/STAT signaling is involved in the ischemia/reperfusion injury in adult rat myocardium.
Methods and Results— We report here that 2 components of the JAK/STAT signaling pathway, namely STAT 5A and STAT 6, are selectively activated in the rat heart subjected to ischemia/reperfusion. The activated STATs bind to a conserved nucleotide sequence (St domain) in the promoter of the angiotensinogen (ANG) gene and consequently upregulate the level of ANG mRNA. Treatment of the hearts with losartan (4.5 µmol/L), an AT1 blocker, or with tyrphostin AG490 (5 µmol/L), an inhibitor of JAK 2 phosphorylation, results in loss of the STAT/ANG promoter binding activity and an upregulated level of ANG mRNA. Hearts treated with the JAK 2 inhibitor tyrphostin AG490 showed a reduction in myocardial infarct size and in number of cardiomyocytes undergoing apoptosis. The treated hearts also showed a recovery in functional hemodynamics of the myocardium.
Conclusions— These findings suggest that activation of the JAK/STAT signaling pathway is a significant contributing factor to the pathogenesis of myocardial ischemia and that interference in activation of the pathway potentiates recovery in cardiac function.
Key Words: ischemia • reperfusion • signal transduction • renin • angiotensin
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