Salusin-\u03b2 contributes to oxidative stress and inflammation in diabetic cardiomyopathy

Ming-Xia Zhao,Guo-Qing Zhu,Li Ling,Feng Zhang,Yue-Hua Li,Yu-Ming Kang,Qi Chen,Xiao-Qing Xiong,Bing Zhou

doi:10.1038/cddis.2017.106

Ming-Xia Zhao, Guo-Qing Zhu + Show 7 more

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https://doi.org/10.1038/cddis.2017.106

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Abstract

Salusin-β accelerates inflammatory responses in vascular endothelial cells, and increases oxidative stress in vascular smooth muscle cells. Plasma salusin-β levels were increased in diabetic patients. This study was designed to determine whether salusin-β is involved in the pathogenesis of diabetic cardiomyopathy (DCM), and whether knockdown of salusin-β attenuates cardiac inflammation and oxidative stress in rats with DCM. H9c2 or neonatal rat cardiomyocytes were incubated with 33.3 mM of glucose to mimic the high glucose (HG) in diabetes. Streptozotocin and high-fat diet were used to induce type 2 diabetes in rats. HG induced salusin-β expression in H9c2 cells. Salusin-β caused greater responses of oxidative stress, NFκB activation and inflammation in HG-treated H9c2 cells than these in control H9c2 cells. Diphenyleneiodonium (a NAD(P)H oxidase inhibitor) or N-acetylcysteine (an antioxidant) inhibited the salusin-β-induced NFκB activation and inflammation. Bay11-7082 (a NFκB inhibitor) attenuated salusin-β-induced inflammation but not oxidative stress. Knockdown of salusin-β prevented the HG-induced oxidative stress, NFκB activation and inflammation in neonatal rat cardiomyocytes. Silencing salusin-β with adenoviruse-mediated shRNA had no significant effects on blood glucose and insulin resistance, but attenuated ventricular dysfunction in diabetic rats. Oxidative stress, NFκB activation, inflammation, salusin-β upregulation in myocardium of diabetic rats were prevented by knockdown of salusin-β. These results indicate that salusin-β contributes to inflammation in DCM via NOX2/ROS/NFκB signaling, and that knockdown of salusin-β attenuates cardiac dysfunction, oxidative stress and inflammation in DCM.

Highlights

In diabetic heart, metabolic derangements, impairments in excitation–contraction coupling, loss of normal microvessels and remodeling of the extracellular matrix are involved in contractile dysfunction.[3]
Salusin-β increased the levels of proinflammatory cytokines including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in H9c2 cells
Accumulating evidences suggest increased oxidative stress coupled with activation of downstream pro-inflammatory cytokines have pivotal roles in the development of DCM.[26,27,28,29]

Summary

Introduction

Metabolic derangements, impairments in excitation–contraction coupling, loss of normal microvessels and remodeling of the extracellular matrix are involved in contractile dysfunction.[3]. Salusin-β promotes proliferation of vascular smooth muscle cells (VSMCs) and vascular fibrosis.[12] ROS production in VSMCs mediates salusin-β-induced foam cell formation and monocyte adhesion,[13] VSMCs migration and intimal hyperplasia after vascular injury.[14] Knockdown of salusin-β reduces ROS production in injured carotid arteries in rats.[13] Salusin-β has been implicated in inflammatory response in vascular endothelial cells.[15,16] Patients with diabetes displayed a distinctly increase in plasma salusin-β levels.[17] Salusin-β is widely distributed in a host of tissues,[8] and can be synthesized locally in the muscle cells of the heart.[18] It has been found that salusin-β contributes to the development of coronary ligationinduced myocardial infarction in rats, and inhibition of endogenous salusin-β may be useful to suppress ventricular remodeling after myocardial ischemia.[19] We hypothesized that salusin-β may have a critical role in DCM.

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Results

Conclusion