Activation of autophagy inhibits NLRP3 inflammasome activation and attenuates myocardial ischemia‐reperfusion injury in diabetic rats

BACKGROUND: Diabetic hearts are more vulnerable to ischemia/reperfusion injury (I/RI). The activation of NLRP3 inflammasome can mediate inflammatory process, and hence may contribute to myocardial I/RI. Activation of autophagy can eliminate excess ROS and alleviate myocardial I/RI in diabetes.The study aimed to investigate whether the activation of autophagy can alleviate diabetic myocardial I/RI via inhibition of NLRP3 inflammasome activation. METHODS AND RESULTS: A dose of 65mg/kg streptozotocin was given via tail vein injection to establish type 1 diabetes model in the rats. The left anterior descending coronary artery was ligated for 30 minutes followed by reperfusion for 2 hours to establish myocardial I/RI model. H9C2 cardiomyocytes were exposed to high glucose (HG, 30 mM) and subjected to hypoxia/reoxygenation (H/R, 6 hours hypoxia followed by 4 hours reoxygenation). The diabetic rats demonstrated significant inhibition of cardiac autophagy (decreased LC3 / and increased p62) that was concomitant with increased activation of NLRP3 inflammasome (increased NLRP3, ASC, cleaved caspase-1, IL-18, IL-1beta) and more severe myocardial I/RI (elevated CK-MB, LDH, and larger infarct size). However, administration of rapamycin, an inhibitor of the autophagy, to activate autophagy resulted in the inhibition of NLRP3 inflammasome, and finally alleviated myocardial I/RI. In vitro, high glucose inhibited autophagy, while activated NLRP3 inflammasome in H9C2 cardiomyocytes, and aggravated H/R injury, but rapamycin reversed these adverse effects of high glucose. CONCLUSION: Activation of autophagy can suppress the NLRP3 inflammasome formation, which in turn attenuates myocardial ischemia reperfusion injury in diabetic rats.