Abstract

Both resveratrol and myocyte enhancer factor 2A (MEF2A) may protect vascular endothelial cell (VEC) through activating the expression of SIRT1. However, the relationship between resveratrol and MEF2A is unclear. We aimed to investigate the deeper mechanism of resveratrol in protecting vascular endothelial cells and whether MEF2A plays a key role in the protective function of resveratrol. Human umbilical vein endothelial cell (HUVEC) was used for in vitro study, and small interfere RNA was used for silencing MEF2A. Silencing MEF2A in the vascular endothelium (VE) of ApoE−/− mice was performed by tail injection with adeno associated virus expressing si-mef2a-shRNA. The results showed that treatment of HUVEC with resveratrol significantly up-regulated MEF2A, and prevented H2O2-induced but not siRNA-induced down-regulation of MEF2A. Under various experimental conditions, the expression of SIRT1 changed with the level of MEF2A. Resveratrol could rescue from cell apoptosis, reduction of cell proliferation and viability induced by H2O2, but could not prevent against that caused by silencing MEF2A with siRNA. Silencing MEF2A in VE of apoE−/− mice decreased the expression of SIRT1, increased the plasma LDL-c, and abrogated the function of resveratrol on reducing triglyceride. Impaired integrity of VE and aggravated atherosclerotic lesion were observed in MEF2A silenced mice through immunofluorescence and oil red O staining, respectively. In conclusion, resveratrol enhances MEF2A expression, and the upregulation of MEF2A is required for the endothelial protective benefits of resveratrol in vitro via activating SIRT1. Our work has also explored the in vivo relevance of this signaling pathway in experimental models of atherosclerosis and lipid dysregulation, setting the stage for more comprehensive phenotyping in vivo and further defining the molecular mechanisms.

Highlights

  • Resveratrol is a polyphenol compound that can be obtained from several dietary sources, such as grapes, apples, blueberries, plums, raspberries and peanuts, and has a variety of healthpromoting effects [1]

  • A large number of studies have confirmed that resveratrol is a strong protector of vascular endothelium, and its main molecular mechanisms include increasing the production of nitric oxide (NO) in vascular endothelium by up-regulating the expression and activity of NO synthase, down-regulating the synthesis of endothelin-1 to reduce vasoconstriction and blood pressure [1, 8], promoting mitochondrial biosynthesis and reducing the production of mitochondrial superoxides [9], preventing arterial aging by reducing the activity of PRR-ACE-AngII axis and activating ACE2-Ang-(1–7)-ATR2-MasR axis [10], reducing vascular endothelial oxidative stress by up-regulating the expression of Sirtuin1 (SIRT1), and delaying vascular endothelial cell senescence [11]

  • In vascular endothelial cells (VEC), myocyte enhancer factor 2A (MEF2A) is considered to be the key transcriptional activator upstream of SIRT1, and resveratrol can effectively stimulate the expression of SIRT1, so does resveratrol up-regulate the expression of SIRT1 and protect VEC depending on stimulating the expression of MEF2A? In this study, we revealed that resveratrol up-regulated SIRT1 expression, functioned anti-apoptosis and anti-atherosclerotic lesions depending on up-regulating MEF2A expression

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Summary

Introduction

Resveratrol is a polyphenol compound that can be obtained from several dietary sources, such as grapes, apples, blueberries, plums, raspberries and peanuts, and has a variety of healthpromoting effects [1]. Evidences from a large number of basic scientific studies and more than 240 clinical studies support the beneficial effects of resveratrol against chronic diseases such as cardiovascular disease, diabetes, hypertension, Alzheimer’s disease, liver disease, kidney disease and cancer [2, 3]. Among these diseases, aging is the most common risk factor, which is usually related to the accumulation of reactive oxygen species (ROS), the increase of inflammatory lesions, the abnormality of cell proliferation and the altered angiogenesis [4,5,6]. A large number of studies have confirmed that resveratrol is a strong protector of vascular endothelium, and its main molecular mechanisms include increasing the production of nitric oxide (NO) in vascular endothelium by up-regulating the expression and activity of NO synthase (eNOS), down-regulating the synthesis of endothelin-1 to reduce vasoconstriction and blood pressure [1, 8], promoting mitochondrial biosynthesis and reducing the production of mitochondrial superoxides [9], preventing arterial aging by reducing the activity of PRR-ACE-AngII axis and activating ACE2-Ang-(1–7)-ATR2-MasR axis [10], reducing vascular endothelial oxidative stress by up-regulating the expression of Sirtuin (SIRT1), and delaying vascular endothelial cell senescence [11]

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