Activation of autophagy inhibits nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome activation and attenuates myocardial ischemia‐reperfusion injury in diabetic rats

• DOI: 10.1111/jdi.13235
• Publication Date: 2020-02-17T01:54:41Z
• Authors: Dengwen Zhang; Yi He; Xiaodong Ye; Yin Cai; Jindong Xu; Liangqing Zhang; Mingyi Li; Hao Liu; Sheng Wang; Zhengyuan Xia
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome; Inflammasomes; Myocardial ischemia‐reperfusion injury; Apoptosis; Myocardial Reperfusion Injury; Articles; RC648-665; Diseases of the endocrine glands. Clinical endocrinology; Diabetes Mellitus, Experimental; Rats; 3. Good health; Rats, Sprague-Dawley; Diabetic myocardium; 03 medical and health sciences; NLR Family, Pyrin Domain-Containing 3 Protein; Autophagy; Animals; Myocytes, Cardiac; Reactive Oxygen Species; Signal Transduction

AbstractAims/IntroductionDiabetic hearts are more vulnerable to ischemia‐reperfusion injury (I/RI). The activation of nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) inflammasome can mediate the inflammatory process, and hence might contribute to myocardial I/RI. Activation of autophagy can eliminate excess reactive oxygen species and alleviate myocardial I/RI in diabetes. The present study aimed to investigate whether the activation of autophagy can alleviate diabetic myocardial I/RI through inhibition of NLRP3 inflammasome activation.Materials and MethodsA dose of 65 mg/kg streptozotocin was given by tail vein injection to establish a type 1 diabetes model in the rats. The left anterior descending coronary artery was ligated for 30 min followed by reperfusion for 2 h to establish a myocardial I/RI model. H9C2 cardiomyocytes were exposed to high glucose (33 mmol/L) and subjected to hypoxia–reoxygenation (6 h hypoxia followed by 4 h reoxygenation).ResultsThe diabetic rats showed significant inhibition of cardiac autophagy (decreased LC3‐II/I and increased p62) that was concomitant with increased activation of NLRP3 inflammasome (increased NLRP3, apoptosis‐related spots protein cleaved caspase‐1, interleukin‐18, interleukin‐1β) and more severe myocardial I/RI (elevated creatine kinase myocardial band, lactate dehydrogenase 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 activating NLRP3 inflammasome in H9C2 cardiomyocytes and aggravating hypoxia–reoxygenation injury, but rapamycin reversed these adverse effects of high glucose.ConclusionActivation of autophagy can suppress the formation of NLRP3 inflammasome, which in turn attenuates myocardial ischemia‐reperfusion injury in diabetic rats.