ag-490 and Myocardial-Ischemia

To investigate the role of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in the cardioprotective mechanisms of exercise preconditioning (EP).. Eighty male Sprague-Dawley (SD) rats were randomized into the Group control, Group EE, Group EP+EE, Group EP+EE+AG, and Group EE+AG. By using 3 days of intermittent treadmill exercise, this study established the EP animal model. Rats were subjected to run to exhaustion on the treadmill at 30 m/min with 0% grade as an exhaustive exercise (EE) protocol. The myocardial injury induced by exhaustive exercise was produced 24 h after EP. JAK2 inhibitor (AG490, 3 mg/kg) was injected before EP. Serum cardiac troponin I (cTnI) levels and hematoxylin basic fuchsine picric acid (HBFP) staining were used to observe the degree of myocardial ischemia. TUNEL, Bcl2, and cleaved caspase-3 levels were used to evaluate the change of myocardial apoptosis. Moreover, the phosphorylations of JAK2 and STAT3 were analyzed as possible mechanisms that might explain the EP-induced cardioprotection.. EP significantly attenuated the exhaustive exercise-induced myocardial ischemia injury, associated with lower serum cTnI levels, decreased myocardial infarct area, reduced myocardial apoptosis, increased Bcl2 level, decreased cleaved caspase-3 level, and the increased phosphorylations of JAK2 and STAT3. Treatment with AG490 abolished the cardioprotective effects and the enhanced phosphorylations of JAK2 and STAT3 induced by EP.. EP plays its cardioprotective role via activating the JAK2/STAT3 signaling pathway, reducing the apoptosis of myocardial cells and alleviating myocardial ischemia injury.

Topics: Animals; Apoptosis; Caspase 3; Janus Kinase 2; Male; Myocardial Ischemia; Myocardium; Phosphorylation; Physical Conditioning, Animal; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; Troponin I; Tyrphostins

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.. 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 micromol/L), an AT(1) blocker, or with tyrphostin AG490 (5 micromol/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.. 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.

Topics: Angiotensinogen; Animals; DNA-Binding Proteins; Enzyme Inhibitors; In Vitro Techniques; Janus Kinase 2; Male; Milk Proteins; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Phosphorylation; Promoter Regions, Genetic; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Rats; RNA, Messenger; Signal Transduction; STAT5 Transcription Factor; STAT6 Transcription Factor; Trans-Activators; Tyrphostins; Up-Regulation