Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway

Abstract

BackgroundPostconditioning (PostC) inhibits myocardial apoptosis after ischemia-reperfusion (I/R) injury. The JAK2-STAT3 pathway has anti-apoptotic effects and plays an essential role in the late protection of preconditioning. Our aim was to investigate the anti-apoptotic effect of PostC after prolonged reperfusion and the role of the JAK2-STAT3 pathway in the anti-apoptotic effect of PostC.MethodsWistar rats were subjected to 30 minutes ischemia and 2 or 24 hours (h) reperfusion, with or without PostC (three cycles of 10 seconds reperfusion and 10 seconds reocclusion at the onset of reperfusion). Separate groups of rats were treated with a JAK2 inhibitor (AG490) or a PI3K inhibitor (wortmannin) 5 minutes before PostC. Immunohistochemistry was used to analyze Bcl-2 protein levels after reperfusion. mRNA levels of Bcl-2 were detected by qRT-PCR. TTC staining was used to detect myocardial infarction size. Myocardial apoptosis was evaluated by TUNEL staining. Western-blot was used to detect p-STAT3 and p-Akt levels after reperfusion.ResultsThere was more myocardial apoptosis at 24 h vs 2 h after reperfusion in all groups. PostC significantly reduced myocardial apoptosis and elevated Bcl-2 levels at both 2 and 24 hours after reperfusion. PostC increased p-STAT3 and p-Akt levels after reperfusion. Administration of AG490 reduced p-STAT3 and p-Akt levels and attenuated the anti-apoptotic effect of PostC. Wortmannin also reduced p-Akt levels and attenuated the anti-apoptotic effect of PostC but had no effect on p-STAT3 levels. AG490 abrogated the up-regulation of Bcl-2 by PostC.ConclusionPostC may reduce myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway. As a downstream target of JAK2 signaling, activation of PI3K/Akt pathway may be necessary in the protection of PostC.

TCF7L2 promotes beta cell regeneration in human and mouse pancreas

“…The JAK2 inhibitor AG490 was associated with a significant reduction in GLP1-and TCF7L2-induced STAT3 phosphorylation. Downstream activation of AKT, which is induced by GLP1 and TCF7L2 in islets [4,6,26] and linked to STAT3 signalling [27], was also blocked by the JAK2 inhibitor (Fig. 7d).…”

Mitochondrial Pathways, Permeability Transition Pore, and Redox Signaling in Cardioprotection: Therapeutic Implications

“…We were among the first to report a Bcl-2 increase and cleaved caspase-3 decrease in PostC (274). It has been also reported that PostC may reduce myocardial apoptosis during reperfusion via a JAK-STAT-3-Bcl-2 pathway (355). Further studies focusing on other proteins of the Bcl-2 family may be helpful to define the long-term benefit of PostC against apoptosis (192,338).…”

“…These studies suggest an important role in reperfusion-induced apoptosis. Both PreC and PostC limit reperfusion injury affecting all form of cell death, including apoptosis (6,274,355,392). Of course, reperfusion must be applied as soon as possible.…”

Curcumin inhibits autophagy and apoptosis in hypoxia/reoxygenation-induced myocytes

“…The Bcl-2 family protein, Bax, is a pro-apoptotic protein, which forms complexes with other proteins in the mitochondrial outer membrane, promoting the release of pro-apoptotic molecules, including cytochrome C, and activates apoptosis (29). Bcl-2 is an anti-apoptotic molecule that reduces myocardial apoptosis during reperfusion (30). Bcl-2 inhibits the action of Bax through direct or indirect mechanisms and reduces cell death (31,32).…”