Autophagy is a well-conserved self-protection process that plays an important role in cardiovascular diseases. Excessive autophagy during myocardial ischemia/reperfusion injury (MIRI) induces calcium overload and the overactivation of an autophagic response, thereby aggravating cardiomyocyte damage. Polycystin-2 (PC2) is a Ca2+-permeable nonselective cation channel implicated in the regulation of autophagy. In the present study, autophagy was upregulated in myocardial ischemia/reperfusion in vivo and in vitro. PC2 knockdown using adeno-associated virus 9 particles containing Pkd2 short hairpin RNA infection markedly ameliorated MIRI, evidenced by reduced infarct size, diminished morphological changes, decreased cTnI levels, and improved cardiac function. Silencing PC2 reduced the autophagic flux in H9c2 cells. PC2 overexpression-mediated autophagic flux was inhibited by intracellular Ca2+ chelation with BAPTA-AM. Furthermore, PC2 ablation upregulated p-Akt (Ser473) and downregulated Beclin 1 in H/R. BAPTA-AM downregulated p-Akt(Ser473) and upregulated Beclin 1in PC2-overexpressing H9c2 cells. Moreover, the Akt inhibitor MK2206 abolished the BAPTA-AM-blunted PC2-dependent control of autophagy. Collectively, these results indicated that blockade of PC2 may be associated with the Ca2+/Akt/Beclin 1 signaling, thereby inhibiting excessive autophagy and serving as a potential strategy for mitigating MIRI.
Keywords: Autophagy; Calcium; Cardiovascular disease; Myocardial ischemia/reperfusion injury; Polycystin-2.
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