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Theranostics 2021; 11(18):8624-8639. doi:10.7150/thno.48561 This issue Cite

Research Paper

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

Meng Zhang¹, Wenhai Sui¹, Yanqiu Xing², Jing Cheng³, Cheng Cheng¹, Fei Xue¹, Jie Zhang¹, Xiaohong Wang¹, Cheng Zhang^1✉, Panpan Hao^1✉, Yun Zhang^1✉

1. The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
2. Department of Geriatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan 250012, Shandong, China.
3. Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.

✉ Corresponding authors: Yun Zhang, MD, PhD, FACC, FESC, FASE, E-mail: zhangyunedu.cn, or Panpan Hao, MD, PhD, E-mail: panda.howedu.cn, or Cheng Zhang, MD, PhD, FACC, FESC, E-mail: zhangcedu.cn, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China More

Abstract

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 autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiac fibroblasts, which were substantially attenuated by Ang IV treatment. However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS.

Conclusions: Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT₄R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.

Keywords: angiotensin IV, diabetic cardiomyopathy, autophagy, FoxO1

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