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

• Published in: Journal of diabetes investigation Vol. 11; no. 5; pp. 1126 - 1136
• Main Authors: Zhang, Dengwen, He, Yi, Ye, Xiaodong, Cai, Yin, Xu, Jindong, Zhang, Liangqing, Li, Mingyi, Liu, Hao, Wang, Sheng, Xia, Zhengyuan
• Format: Journal Article
• Language: English
• Published: Japan John Wiley & Sons, Inc 01.09.2020; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Antibodies; Apoptosis; Autophagy; Cardiomyocytes; Cardiovascular disease; Caspase; Coronary artery; Creatine; Creatine kinase; Dehydrogenases; Deoxyribonucleic acid; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Experimental - complications; Diabetic myocardium; DNA; Glucose; Heart; Homeostasis; Hypoxia; Inflammasomes; Inflammasomes - genetics; Inflammasomes - metabolism; Inflammation; Ischemia; L-Lactate dehydrogenase; Laboratory animals; Lactic acid; Male; Myocardial ischemia; Myocardial ischemia‐reperfusion injury; Myocardial Reperfusion Injury - etiology; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome; Oligomerization; Original; Oxidative stress; Penicillin; Phagocytosis; Proteins; Rapamycin; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reperfusion; Rodents; Signal Transduction; Streptozocin; United States > US; Diabetic myocardium; Myocardial ischemia-reperfusion injury; Nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome
• ISSN: 2040-1116; 2040-1124; 2040-1124
• DOI: 10.1111/jdi.13235

Aims/Introduction Diabetic 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 Methods A 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). Results The 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. Conclusion Activation of autophagy can suppress the formation of NLRP3 inflammasome, which in turn attenuates myocardial ischemia‐reperfusion injury in diabetic rats. Autophagy was inhibited in the myocardium of 8‐week diabetic rats, with activated NLRP3 inflammasome and aggravated myocardial ischemia‐reperfusion injury. Activation of autophagy can reduce the activation of NLRP3 inflammasome and therefore increase the tolerance to myocardial ischemia in diabetes.