Aerobic exercise alleviates diabetic cardiomyopathy via attenuation of P2X4-mediated NLRP3 inflammasome activation and cardiomyocyte pyroptosis

Diabetic cardiomyopathy (DCM) is one of the most prevalent diabetic complications associated with chronic low-grade inflammation. P2X purinergic receptors and NLRP3 inflammasome have been reported to be enriched in DCM hearts. They are regarded as partners in the crime of inflammation and inflammatory type of cell death, pyroptosis. Exercise is an effective nonpharmacological therapy for DCM though the involving mechanisms are ill-defined. The cardioprotective role of exercise may rely heavily on its anti-inflammatory effect. However, whether exercise modulates P2X and NLRP3 inflammasome activation and thus ameliorates DCM pathologies and pyroptosis needs to be clarified entirely. In this study, we found that P2X4/P2X7-NLRP3 is involved in the pathogenesis of DCM. Exercise serves a cardioprotective effect through the inhibition of the P2X4/ROS/NLRP3 signalling pathway. AICAR exerts an inhibitory effect on NLRP3 inflammasome and pyroptosis by simultaneously targeting P2X4 and P2X7, showing an exercise mimic effect. Overall, we proposed novel insights into the therapeutic and preventive effects of early exercise intervention on DCM progress.