title: Inhibition of Mitochondrial Fission and NOX2 Expression Prevent NLRP3 Inflammasome Activation in the Endothelium: The Role of Corosolic Acid Action in the Amelioration of Endothelial Dysfunction.
abstract: Corosolic acid (CRA) is a natural triterpenoid with antioxidative activity. This study was designed to elucidate the mechanism through which CRA protected vessel endothelial homeostasis by combating oxidative stress.
  
  
  
  In endothelial cells, CRA induced dynamin-related protein 1 (Drp1) phosphorylation at Ser637 and thus inhibited mitochondrial fission in response to oxidative stress. It promoted AMP-activated protein kinase (AMPK) activity in an LKB1-dependent manner, and silencing AMPK abrogated its inhibitory effect on Drp1 activation and mitochondrial fission. CRA inhibited the translocation of p47(phox) and p67(phox) and the overexpression of gp91(phox) induced by palmitate (PA), demonstrating its action in suppression of NOX2 activation. Drp1 knockdown reduced PA-induced gp91(phox) expression, while Drp1 induction was also diminished by gp91(phox) knockdown, suggesting the reciprocal relationship between NOX2 and Drp1. Knockdown Drp1 or gp91(phox) attenuated PA-induced NLRP3 induction and enhanced inhibitory effects of CRA. Oral administration of CRA in high-fat diet mice reproduced similar regulation in the aorta endothelium, further confirming its protection on endothelial homeostasis in vivo.
  
  
  
  This study demonstrated that the defect in mitochondrial morphology is associated with the oxidative stress and NLRP3 inflammasome activation in the endothelium. Drp1 and NOX2 regulated each other and worked together to induce NLRP3 inflammasome activation, suggesting that modulation of Drp1 phosphorylation (Ser637) might be a potential therapeutic target for combating oxidative stress in vessel diseases.
  
  
  
  CRA prevented mitochondrial fission by regulation of Drp1 phosphorylation (Ser637) in an AMPK-dependent manner, and this action contributed to blocking NOX2 oxidase signaling and suppressing NLRP3 inflammasome activation in the endothelium. Antioxid. Redox Signal. 24, 893-908.
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .|2 Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing, P.R. China .
authors: Yi
authors: Y
authors: Li
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .|2 Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing, P.R. China .
authors: Zhi-Hui
authors: ZH
authors: Zhou
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .|2 Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing, P.R. China .
authors: Mei-Hong
authors: MH
authors: Chen
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .|2 Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing, P.R. China .
authors: Jie
authors: J
authors: Yang
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .|2 Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing, P.R. China .
authors: Jing
authors: J
authors: Leng
authors: 3 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University , Nanjing, P.R. China .
authors: Guo-Sheng
authors: GS
authors: Cao
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .|2 Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing, P.R. China .
authors: Gui-Zhong
authors: GZ
authors: Xin
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .|2 Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing, P.R. China .
authors: Li-Fang
authors: LF
authors: Liu
authors: 3 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University , Nanjing, P.R. China .
authors: Jun-Ping
authors: JP
authors: Kou
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .|3 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University , Nanjing, P.R. China .
authors: Bao-Lin
authors: BL
authors: Liu
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .
authors: Ping
authors: P
authors: Li
authors: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, P.R. China .
authors: Xiao-Dong
authors: XD
authors: Wen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism; D002478:Cells, Cultured; D034281:Dynamins / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D063154:Mitochondrial Dynamics; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009687:Nuclear Proteins; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D058847:Inflammasomes; D008562:Membrane Glycoproteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; C498751:Nsfl1c protein, rat; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D014315:Triterpenes; C079789:neutrophil cytosol factor 67K; C113861:corosolic acid; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D055372:AMP-Activated Protein Kinases; C519851:Dnm1l protein, rat; D034281:Dynamins