Potential Role of Aerobic Exercise in Attenuating Diabetic Cardiomyopathy via Modulation of P2X4-Mediated NLRP3 Inflammasome Activation and Pyroptosis.

Abstract

Diabetic cardiomyopathy (DCM) is a common diabetic complication associated with chronic low-grade inflammation. Exercise is an effective therapy for DCM, though its mechanisms remain unclear. Here, we demonstrate that exercise mitigates pyroptosis in DCM, potentially by modulating P2X4. Exercise prevented the upregulation of P2X4 and PANX1, inhibited NLRP3 activation, and reduced GSDMD and IL-1β cleavage in DCM mouse hearts, without altering P2X7 levels. In vitro, high glucose alone did not induce significant H9C2 cell death or increase P2X4/P2X7 expression. However, palmitic acid promoted a concentration-dependent increase in P2X4 and NLRP3 expression, caspase-1 activity, and cell necrosis, indicating that lipids drive pyroptosis. A high-fat diet (HFD) model further confirmed a positive correlation between P2X4 expression and NLRP3 activation. Consistent with DCM findings, exercise suppressed P2X4, but not P2X7, in obese mice. Additionally, we observed that exercise and AICAR share a similar mechanism in restraining NLRP3 inflammasome activation by targeting P2X4 and, partially, P2X7, although AICAR did not downregulate P2X7. Overall, our results highlight the critical role of P2X4 in NLRP3-mediated pyroptosis and suggest that exercise ameliorates myocardial inflammation in DCM primarily through P2X4 inhibition.