Myocardial ischemia activates the JAK-STAT pathway through angiotensin II signaling in in vivo myocardium of rats

There have been many studies concerning the hemodynamics and physiological mechanisms in ischemic heart disease, little is known about molecular mecha nisms during myocardial ischemia in in vivo study. As the signal transducti on pathway responsible for myocardial hypertrophy and apoptosis, janus kina se (JAK) and signal transducers and activators of transcription (STAT) are suggested to play an important role. However, whether in vivo activation of JAK-STAT pathway occurs during myocardial ischemia is still unknown. The p urpose of this study was to determine whether myocardial JAK or STAT is act ivated in ischemic heart, and to evaluate the angiotensin blockade on the p athway Myocardial infarction was produced by ligation of the coronary arter y in Wistar rats. After myocardial ischemia, we analysed both activated lev els and total amounts of JAK1, JAK2, STAT1 and STAT3 by Western blot analys es at 0, 5 15, 30, 60, 120 and 240 min. Compared with JAK activities at 0 m in, JAK1 activities were significantly increased at 60 and 120 min (3.0- an d 3.7-fold, respectively, P<0.01). JAK2 and STAT1 activities of ischemic my ocardium were unchanged through the time course. STAT3 activities were incr eased at 5 min (3.3-fold, P<0.01) and markedly enhanced at 30, 60 and 120 m in (4.6-, 7,7- and 8.7-fold, respectively P<0.01). Pretreatment with imidap ril (ACE inhibitor) and candesartan cilexitil (AT1 receptor antagonist) sig nificantly prevented the increase in the phosphorylation of JAK1 at 120 min and STAT3 at 30 and 120 min, Sis-inducing factor (SIF) DNA complex was sup ershifed by specific anti-STAT3 antibody, indicating that increased SIF com plex at least contained activated STAT3 proteins in ischemic myocardium. Im idapril and candesartan cilexitil inhibited the activation of SIF DNA bindi ng at 1 day after coronary ligation, In conclusion, we showed that JAK1 and STAT3 were activated by ischemia from the basal activities in in vivo rat myocardial ischemia model, Imidapril and candesartan cilexitil prevented th e increase in phosphorylated JAK1 and STAT3, thereby suggesting that angiot ensin II, especially angiotensin II type I receptor, partially mediates act ivation of myocardial JAK-STAT pathway in acute myocardial ischemia. (C) 20 01 Academic Press.