Angiotensin IV attenuates diabetic cardiomyopathy via suppressing FoxO1-induced excessive autophagy, apoptosis and fibrosis

作者：Meng Zhang, Wenhai Sui, Yanqiu Xing, Jing Cheng, Cheng Cheng, Fei Xue, Jie Zhang, Xiao‐Hong Wang, Cheng Zhang, Panpan Hao, Yun Liang Zhang · 发表于：Theranostics · 年份：2021 · DOI：10.7150/thno.48561 · 被引用次数：155 · 研究领域：Autophagy in Disease and Therapy、Cardiac Fibrosis and Remodeling、Signaling Pathways in Disease

Rationale: The rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the pathogenesis of diabetic cardiomyopathy, but the role of a member of RAAS, angiotensin IV (Ang IV), in this disease and its underlying mechanism are unclear.This study was aimed to clarify the effects of Ang IV and its downstream mediator forkhead box protein O1 (FoxO1) on diabetic cardiomyopathy.Methods: In vivo, diabetic mice were treated with low-, medium-and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations.In vitro, H9C2 cardiomyocytes and cardiac fibroblasts were treated with different concentrations of glucose, low-, medium-and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS, or their combinations.Results: Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice.Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment.However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration.Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups.Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice.In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive ...