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  2. FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/β5-AKT signaling and reduction of oxidative/nitrosative stress

FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/β5-AKT signaling and reduction of oxidative/nitrosative stress

  • J Mol Cell Cardiol. 2021 Nov;160:27-41. doi: 10.1016/j.yjmcc.2021.06.013.
Chen Lin 1 Yongzhen Guo 1 Yunlong Xia 1 Congye Li 1 Xiaoming Xu 1 Tingting Qi 1 Fuyang Zhang 1 Miaomiao Fan 1 Guangyu Hu 1 Hang Zhao 1 Huishou Zhao 1 Rui Liu 2 Erhe Gao 3 Wenjun Yan 4 Ling Tao 5
Affiliations

Affiliations

  • 1 Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 2 Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
  • 3 Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
  • 4 Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: yanyan517032@163.com.
  • 5 Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: lingtao@fmmu.edu.cn.
Abstract

Irisin, the cleaved form of the fibronectin type III domain containing 5 (FNDC5) protein, is involved in metabolism and inflammation. Recent findings indicated that irisin participated in cardiovascular physiology and pathology. In this study, we investigated the effects of FNDC5/irisin on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. Downregulation of myocardial FNDC5/irisin protein expression and plasma irisin levels was observed in db/db mice compared to db/+ controls. Moreover, echocardiography revealed that db/db mice exhibited normal cardiac systolic function and impaired diastolic function. Adverse structural remodeling, including cardiomyocyte Apoptosis, myocardial fibrosis, and cardiac hypertrophy were observed in the hearts of db/db mice. Sixteen-week-old db/db mice were intramyocardially injected with adenovirus encoding FNDC5 or treated with recombinant human irisin via a peritoneal implant osmotic pump for 4 weeks. Both overexpression of myocardial FNDC5 and exogenous irisin administration attenuated diastolic dysfunction and cardiac structural remodeling in db/db mice. Results from in vitro studies revealed that FNDC5/irisin protein expression was decreased in high glucose (HG)/high fat (HF)-treated cardiomyocytes. Increased levels of inducible nitric oxide synthase (iNOS), NADPH Oxidase 2 (NOX2), 3-nitrotyrosine (3-NT), Reactive Oxygen Species (ROS), and peroxynitrite (ONOO-) in HG/HF-treated H9C2 cells provided evidence of oxidative/nitrosative stress, which was alleviated by treatment with FNDC5/irisin. Moreover, the mitochondria membrane potential (ΔΨm) was decreased and cytochrome C was released from mitochondria with increased levels of cleaved Caspase-3 in HG/HF-treated H9C2 cells, indicating the presence of mitochondria-dependent Apoptosis, which was partially reversed by FNDC5/irisin treatment. Mechanistic studies showed that activation of Integrin αVβ5-AKT signaling and attenuation of oxidative/nitrosative stress were responsible for the cardioprotective effects of FNDC5/irisin. Therefore, FNDC5/irisin mediates cardioprotection in DCM by inhibiting myocardial Apoptosis, myocardial fibrosis, and cardiac hypertrophy. These findings implicate that FNDC5/irisin as a potential therapeutic intervention for DCM, especially in type 2 diabetes mellitus (T2DM).

Keywords

Diabetic cardiomyopathy; FNDC5; Irisin; Oxidative/nitrosative stress; Type 2 diabetes mellitus.

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