JAK/STAT signaling is associated with cardiac dysfunction during ischemia and reperfusion

Background - Activation of the heart renin-angiotensin system (RAS) under p athophysiological conditions has been correlated with the development of is chemic injury. The binding of angiotensin II to its receptors triggers indu ction of several, perhaps multifunctional, intracellular signaling pathways , notable among them the Janus kinase/signal transducer and activator of tr anscription (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 sign aling 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 angiotensi nogen (ANG) gene and consequently upregulate the level of ANG mRNA. Treatme nt of the hearts with losartan (4.5 mu mol/L), an AT, blocker, or with ;tyr phostin AG490 (5 mu mol/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 showe d a reduction in myocardial infarct size and in number of cardiomyocytes un dergoing apoptosis. The treated hearts also showed a recovery in functional hemodynamics of the myocardium. Conclusions - These findings suggest that activation of the JAK/STAT signal ing pathway is a significant contributing factor to the pathogenesis of myo cardial ischemia and that interference in activation of the pathway potenti ates recovery in cardiac function.