Regulating RISK: a role for JAK-STAT signaling in postconditioning?

Abstract

Postconditioning (POC), a novel strategy of cardioprotection against ischemia-reperfusion injury, is clinically attractive because of its therapeutic application at the predictable onset of reperfusion. POC activates several intracellular kinase signaling pathways, including phosphatidylinositol 3-kinase (PI3K)-Akt (RISK). The regulation of POC-induced survival kinase signaling, however, has not been fully characterized. JAK-STAT activation is integral to cardiac ischemic tolerance and may provide upstream regulation of RISK. We hypothesized that POC requires the activation of both JAK-STAT and RISK signaling. Langendorff-perfused mouse hearts were subjected to 30 min of global ischemia and 40 min of reperfusion, with or without POC immediately after ischemia. A separate group of POC hearts was treated with AG 490, a JAK2 inhibitor, Stattic, a specific STAT3 inhibitor, or LY-294002, a PI3K inhibitor, at the onset of reperfusion. Cardiomyocyte-specific STAT3 knockout (KO) hearts were also subjected to non-POC or POC protocols. Myocardial performance (+dP/dt(max), mmHg/s) was assessed throughout each perfusion protocol. Phosphorylated (p-) STAT3 and Akt expression was analyzed by Western immunoblotting. POC enhanced myocardial functional recovery and increased expression of p-STAT3 and p-Akt. JAK-STAT inhibition abrogated POC-induced functional protection. STAT3 inhibition decreased expression of both p-STAT3 and p-Akt. PI3K inhibition also attenuated POC-induced cardioprotection and reduced p-Akt expression but had no effect on STAT3 phosphorylation. Interestingly, STAT3 KO hearts undergoing POC exhibited improved ischemic tolerance compared with KO non-POC hearts. POC induces myocardial functional protection by activating the RISK pathway. JAK-STAT signaling, however, is insufficient for effective POC without PI3K-Akt activation.

Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore

“…One possible interpretation that can be placed on these data is that the JAK/STAT pathway operates upstream of the RISK cascade. Indeed, it has been proposed that JAK/STAT activation, stimulated by postconditioning, may precede Akt phosphorylation and that JAK/ STAT phosphorylation in the absence of RISK activation is insufficient to provide protection (12). More recently, cardioprotection induced by insulin was suggested to involve a close interaction between STAT3 and Akt (11).…”

“…The possibility that alternative cellular mechanisms underlie cardioprotection associated with JAK/STAT activation must, therefore, be considered. Already several potential mechanisms have been proposed, including scenarios in which JAK/STAT activation leads to subsequent activation of the RISK pathway (12,33).…”

Cardioprotection Techniques: Preconditioning, Postconditioning and Remote Con-ditioning (Basic Science)

“…IPost using 5x5 sec cycles of ischemia/reperfusion reduced myocardial infarct size but 3x10 sec cycles did not [219]. Using mice with the same cardiacrestricted STAT-3 deletion, Goodman and colleagues [220] were able to demonstrate improved LV function using the IPost protocol of 3x10 sec cycles of ischemia/reperfusion, suggesting that STAT-3 may not be an obligatory mediator of IPost. The mechanism underlying the acute form of myocardial protection mediated by the JAK-STAT pathway is unclear but may relate to as yet unidentified mitochondrial effects [221].…”

“…The Survival Activating Factor Enhancement (SAFE) pathway, which comprises the TNF-receptor and Janus Kinase (JAK)-Signal transducer and activator of transcription (STAT) pathway, has also been linked to cardioprotection elicited by IPost [219,220]. Experimental studies have reported that pharmacologically inhibiting the JAK-STAT pathway at the onset of myocardial reperfusion abrogates the infarct-limiting effects of IPost [219,220].…”

“…Experimental studies have reported that pharmacologically inhibiting the JAK-STAT pathway at the onset of myocardial reperfusion abrogates the infarct-limiting effects of IPost [219,220]. However, mice with a cardiac-specific STAT3 deletion were found to still be amenable to the infarct-limiting effects of IPost, providing a suitable IPost protocol was used i.e.…”