Irisin inhibits high glucose-induced endothelial-to-mesenchymal transition and exerts a dose-dependent bidirectional effect on diabetic cardiomyopathy.

Xue Liu,Ming‐Xiang Zhang,Yu‐Xia Zhao,Na Li,Yu‐Guo Chen,Haroon Mujahid,Bing Rong,Nai‐Lin Li,Peng Li,Dong‐Qi Tang,Xiao‐Ping Ji,Qi Wang,Er‐Shun Liang,Qing‐Hua Lu,Wei Zhang

doi:10.1111/jcmm.13360

Abstract

Emerging evidence indicates that irisin provides beneficial effects in diabetes. However, whether irisin influences the development of diabetic cardiomyopathy (DCM) remains unclear. Therefore, we investigated the potential role and mechanism of action of irisin in diabetes‐induced myocardial dysfunction in mice. Type 1 diabetes was induced in mice by injecting streptozotocin, and the diabetic mice were administered recombinant r‐irisin (low or high dose: 0.5 or 1.5 μg/g body weight/day, I.P.) or PBS for 16 weeks. Irisin treatment did not alter blood glucose levels in the diabetic mice. However, the results of echocardiographical and histopathological assays indicated that low‐dose irisin treatment alleviated cardiac fibrosis and left ventricular function in the diabetic mice, whereas high‐dose irisin failed to mitigate the ventricular function impairment and increased collagen deposition. The potential mechanism underlying the effect of low‐dose irisin involved irisin‐mediated inhibition of high glucose‐induced endothelial‐to‐mesenchymal transition (EndMT); conversely, high‐dose irisin treatment enhanced high glucose‐induced MMP expression by stimulating MAPK (p38 and ERK) signalling and cardiac fibroblast proliferation and migration. Low‐dose irisin alleviated DCM development by inhibiting high glucose‐induced EndMT. By contrast, high‐dose irisin disrupted normal MMP expression and induced cardiac fibroblast proliferation and migration, which results in excess collagen deposition. Thus, irisin can inhibit high glucose‐induced EndMT and exert a dose‐dependent bidirectional effect on DCM.

Highlights

Diabetes mellitus is recognized to increase the risk of cardiomyopathy independently of coronary artery disease, hypertension and atherosclerosis [1]
Serum irisin level has been demonstrated to be lower in patients with type 2 DM than in healthy controls [21], whereas elevated circulating irisin levels have been documented in patients with type 1 diabetes mellitus (T1DM), in female patients [17]
To determine whether ririsin can prevent the development of the characteristic changes of type I diabetic cardiomyopathy (DCM), we used mice that were treated with r-irisin to counteract the effects of DCM before the disease model was already established, and we used two doses of irisin (0.5 and 1.5 lg/g body weight/day) and continued the experiment for 8 weeks

Summary

Introduction

Diabetes mellitus is recognized to increase the risk of cardiomyopathy independently of coronary artery disease, hypertension and atherosclerosis [1]. In DCM, which increases morbidity and mortality risk in diabetic patients, the pathological process presents myocardial diastolic and systolic dysfunction, left ventricular (LV) hypertrophy, and fibrosis [1, 2]. Numerous complex molecular mechanisms have been proposed to investigate the structural and functional alterations in the diabetic heart, including increased perivascular and intermyofibrillar fibrosis and myocardial cell death in human diabetes [3, 4]. The mechanisms responsible for the myocardial fibrosis underlying the accumulation of extracellular matrix (ECM) proteins ( collagen types I and III) include excess collagen production, reduced a 2017 The Authors.

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Results

Conclusion