Nitrative Modification of Caveolin-3: A Novel Mechanism of Cardiac Insulin Resistance and a Potential Therapeutic Target Against Ischemic Heart Failure in Prediabetic Animals

作者：Zhijun Meng, Zhen Zhang, Jianli Zhao, Caihong Liu, Peng Yao, Ling Zhang, Dina Xie, Wayne Bond Lau, Jumpei Tsukuda, Theodore A. Christopher, Bernard S. López, Di Zhu, Demin Liu, John Ry Zhang, Erhe Gao, Harry Ischiropoulos, Walter J. Koch, Xinliang Ma, Yajing Wang · 发表于：Circulation · 年份：2023 · DOI：10.1161/circulationaha.122.063073 · 被引用次数：36 · 研究领域：Caveolin-1 and cellular processes、Cardiovascular Function and Risk Factors、Peroxisome Proliferator-Activated Receptors

Background: Myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlying molecular mechanisms remain unclear. Recent studies demonstrate that the diabetic heart is resistant to other cardioprotective interventions, including adiponectin and preconditioning. The “universal” resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad prosurvival signaling cascades. Cav (Caveolin) is a scaffolding protein coordinating transmembrane signaling transduction. However, the role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. Methods: Wild-type and gene-manipulated mice were fed a normal diet or high-fat diet for 2 to 12 weeks and subjected to myocardial ischemia and reperfusion. Insulin cardioprotection was determined. Results: Compared with the normal diet group, the cardioprotective effect of insulin was significantly blunted as early as 4 weeks of high-fat diet feeding (prediabetes), a time point where expression levels of insulin-signaling molecules remained unchanged. However, Cav3/insulin receptor-β complex formation was significantly reduced. Among multiple posttranslational modifications altering protein/protein interaction, Cav3 (not insulin receptor-β) tyrosine nitration is prominent in the prediabetic heart. Treatment of cardiomyocytes with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride reduced the signalsome compl...