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 role of the peptide hormone angiotensin (AngII) in promoting myocardial hypertrophy is well documented. Our studies demonstrate that AngII uses a signaling pathway in cardiac myocytes in which the promoter of the gene encoding its prohormone, angiotensinogen, serves as the target site for activated signal transduction and activator of transcription (STAT) proteins. Gel mobility-shift assay revealed that STAT3 and STAT6 are selectively activated by AngII treatment of cardiomyocytes in culture and bind to a sequence motif (St-domain) in the angiotensinogen promoter to activate its transcription in transient transfection assay. We have also observed a dramatic increase in the St-domain binding activity of STAT proteins in the hypertrophied heart of the genetically hypertensive rat relative to that of the aged-matched normotensive strain WKY, providing a compelling argument in favor of the linkage of STAT pathway to the heart tissue autocrine AngII loop. These studies thus uncover a mechanism by which the activation of a selective set of STATs underlies mobilization of the gene activation program intrinsic to cardiac hypertrophy.

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