Causal relevance of the JAK/STAT pathway for cardioprotection via cold acclimation

Cardioprotective effect of cold acclimation (5 weeks; 9 °C; CA) and the same effect persisting 2 weeks after recovery from CA (CAR) are induced by different mechanisms. We showed that salvage β2-adrenoceptor/Gi/Akt pathway is only involved in the mechanism of cardioprotection after CAR. Since the mechanism of CA-elicited cardioprotection is not known, we examined the role of JAK2/STAT3 pathway. Male Wistar rats exposed to CA and controls (24 °C) were treated with the JAK2 inhibitor AG490 affecting downstream STAT3 signaling in the heart (5 mg/kg/day) for three days prior to the end of experiment. AG490 administration abolished CA-elicited reduction of infarct-size and significant improvement of MPT pore opening. IL-6, as the main STAT3 upstream effector, was upregulated by CA, and AG490 reversed its level. CA had no effect on IL-1β and TNF-α, but was upregulated by AG490 in controls, and downregulated in CA-AG490 group. CA also reduced pro-apoptotic p38-MAPK, which was abolished by AG490 administration. Spatial expression analyses revealed CA-elicited translocation of total-STAT3 from mitochondria to sarcolemma compartment which was eliminated by JAK2/STAT3 inhibition. However, CA-induced loss of pSTAT3Y705 from sarcolemma compartment, and loss of pSTAT3S727 from nucleus. These results identify non-genomic, mitochondria-associated STAT3 activity as a confirmed mechanism of CA-elicited cardioprotection.