Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses

doi:10.1016/j.yjmcc.2015.07.015

Journal of Molecular and Cellular Cardiology

Volume 87, October 2015, Pages 138-147

https://doi.org/10.1016/j.yjmcc.2015.07.015 Get rights and content

Highlights

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Reduced irisin level and impaired endothelial function are seen in T2DM mice.
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Irisin protects endothelial function via reducing oxidative/nitrative stresses.
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Irisin inhibits activation of PKC-β/NADPH oxidase and NF-κB/iNOS pathways.

Abstract

Vascular complications are the major causes of death in patients with diabetes, and endothelial dysfunction is the earliest event in vascular complications of diabetes. It has been reported that plasma irisin level is significantly reduced in patients with type 2 diabetic patients. The present study aimed to investigate whether irisin improved endothelial function in type 2 diabetes as well as the underlying mechanisms. The type 2 diabetes model was established by feeding C57BL/6 mice with high-fat diet. The type 2 diabetic mice exhibited reduced serum irisin level and impaired endothelial function. Irisin treatment (0.5 mg/kg/d) for two weeks improved vascular function based on the evaluation of endothelium-dependent vasorelaxation and p-VASP levels. To investigate the direct endothelial protective effects of irisin, diabetic aortic segments were incubated with irisin (1 μg/ml) ex vivo. Exposure to irisin improved endothelium-dependent vasorelaxation of diabetic aortas. Mechanically, the diabetic aortic segments exhibited increased oxidative/nitrative stresses. Irisin reduced the diabetes-induced oxidative/nitrative stresses evidenced by reducing overproduction of superoxide and peroxynitrite, and down-regulation of iNOS and gp91^phox. To further investigate the protective effects of irisin on endothelial cells and the underlying mechanisms, human umbilical vein endothelial cells (HUVECs) cultured in high-glucose/high-fat (HG/HF) medium were pre-incubated with irisin. Irisin (1 μg/ml) reduced the oxidative/nitrative stresses and apoptosis induced by HG/HF in HUVECs probably via inhibiting activation of PKC-β/NADPH oxidase and NF-κB/iNOS pathways. Taken together, irisin alleviates endothelial dysfunction in type 2 diabetes partially via reducing oxidative/nitrative stresses through inhibiting signaling pathways implicating PKC-β/NADPH oxidase and NF-κB/iNOS, suggesting that irisin may be a promising molecule for the treatment of vascular complications of diabetes.

Introduction

Type 2 diabetes mellitus (T2DM) has become a serious threat to public health with rapidly increasing incidence worldwide [1], [2], [3]. Diabetic patients have an up to tenfold increased risk compared to age-matched non-diabetic patients to experience cardiovascular events, and cardiovascular complications are the principle causes of death and disability in T2DM patients [4]. Up to now, the molecular link between T2DM and increased cardiovascular injury remains elusive.

Endothelial dysfunction characterized by reduced nitric oxide (NO) bioavailability is the earliest pathologic event in many cardiovascular diseases and contributes significantly to the initiation and progression of many vascular injuries, including diabetic vascular complications [5]. Theoretically, improving endothelial function is an attractive therapeutic intervention in preventing and treating of cardiovascular diseases. However, effective treatment is rather limited and identifying novel therapeutic targets is greatly desired.

Irisin is a newly identified hormone secreted by myocytes. As a proteolytic hormone derivative of the fibronectin type III domain containing 5 (FNDC5) gene, irisin has been demonstrated to be induced by exercise, and to then directly stimulate browning of white adipocytes and thermogenesis [6]. It has been reported that over-expression of irisin increases the total body energy expenditure, induces weight loss, improves glucose tolerance, and alleviates insulin resistance in high fat-fed mice [7]. More interestingly, the level of serum irisin in T2DM patients is significantly lower than that in non-diabetic control subjects [8], [9]. In addition, it has been shown that serum irisin is negatively associated with hyperglycemia, triglyceridemia, and visceral adiposity in type 2 diabetic patients [10]. However, whether reduced irisin level observed in diabetic patients is pathologically important in diabetic cardiovascular injury remains unknown, and whether supplementation of irisin may effectively protect endothelial function remains unclear.

Therefore, the aims of the current study are to clarify whether reduced irisin is causatively related to endothelial dysfunction in T2DM, to investigate whether irisin has direct vascular protective role, and if so, to indentify the molecular mechanisms involved.

Section snippets

Animal care and drug treatment

All experiments in this study were performed according to the National Institutes of Health Guidelines on the Use of Laboratory Animals (NIH publication No. 85-23, revised 1996), and were approved by the Fourth Military Medical University Committee on Animal Care. Male C57/BL6 mice at the age of 4–6 weeks were purchased from the Laboratory Animal Center of the Fourth Military Medical University, and maintained in a temperature-controlled barrier facility with a 12-hour light/dark cycle. Mice

Irisin improved metabolic disturbances in type 2 diabetic mice

Mice fed with HF diet developed type 2 diabetes characterized by increased body weight (Fig. 1A), fasting blood glucose (Table 1), and fasting serum insulin (Fig. 1B) compared with control mice fed with chow diet. In addition, impaired intraperitoneal glucose tolerance test (IPGTT) results (Fig. 1C) and increased total cholesterol and triglycerides (Table 1) were also observed in the mice fed with HF diet. The diabetic mice treated with irisin exhibited reduced body weight (Fig. 1A, 29.1 ± 1.3

Discussion

In the present study, we provided evidence showing that irisin had protective effects on endothelia in type 2 diabetes, partially through reducing oxidative/nitrative stress and inhibiting activation of PKC-β/NADPH oxidase and NF-κB/iNOS pathways. Our results suggest that irisin may be effective in the treatment of diabetic vascular complications.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia, hyperlipidemia, glucose intolerance, and insulin resistance.

Conflict of interest

None declared.

Acknowledgment

This work was supported by Program for National Science Fund for Distinguished Young Scholars of China (Grant No. 81225001), National Key Basic Research Program of China (973 Program, Grant No. 2013CB531204), New Century Excellent Talents in University (Grant No. NCET-11-0870), Program for Changjiang Scholars and Innovative Research Team in University (Grant No. PCSIRT1053), Key Science and Technology Innovation Team in Shaanxi Province (Grant No. IRT-14208), National Natural Science Foundation

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¹: The first 3 authors contributed equally to this work.

View full text

Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses

Highlights

Abstract

Introduction

Section snippets

Animal care and drug treatment

Irisin improved metabolic disturbances in type 2 diabetic mice

Discussion

Conflict of interest

Acknowledgment

Lancet

J. Diabetes Complicat.

Diabetes Res. Clin. Pract.

J. Mol. Cell. Cardiol.

Free Radic. Biol. Med.

Biochim. Biophys. Acta

Curr. Opin. Pharmacol.

Redox Biol.

Cell Metab.

Protein kinase C-beta contributes to impaired endothelial insulin signaling in humans with diabetes mellitus

Circulation

Targeting vascular endothelial cell insulin resistance in type 2 diabetes mellitus: is protein kinase cβ the bullseye for reducing vascular risk in diabetes?

Circulation

The pathobiology of diabetic vascular complications—cardiovascular and kidney disease

J. Mol. Med.

Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity

Am. J. Physiol. Endocrinol. Metab.

Expression of the irisin precursor FNDC5 in skeletal muscle correlates with aerobic exercise performance in patients with heart failure

Circ. Heart Fail.

A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis

Nature

Effects of obesity, diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue: in vivo and in vitro studies

J. Physiol.

Reduced cardioprotective action of adiponectin in high-fat diet-induced type II diabetic mice and its underlying mechanisms

Antioxid. Redox Signal.

Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling

Diabetes