Myocyte enhancer factor 2A delays vascular endothelial cell senescence by activating the PI3K/p-Akt/SIRT1 pathway.

Benrong Liu,Lin Wang,Xiaohui Chen,Yun Zhong,Lihua Pang,Shi-Ming Liu,Yujuan Xiong,Chaowei Tian,Wenyi Jiang,Wenchao Ou,Chongyu Zhang

doi:10.18632/aging.102015

Abstract

Myocyte enhancer factor 2A (MEF2A) dysfunction is closely related to the occurrence of senile diseases such as cardiocerebrovascular diseases, but the underlying molecular mechanism is unclear. Here, we studied the effects of MEF2A on the senescent phenotype of vascular endothelial cells (VEC) and downstream signaling pathway, and the association between plasma MEF2A levels and coronary artery disease (CAD). Results showed that MEF2A silencing promoted cell senescence and down-regulated PI3K/p-AKT/Sirtuin 1 (SIRT1) expression. MEF2A overexpression delayed cell senescence and up-regulated PI3K/p-AKT/SIRT1. Hydrogen peroxide (H2O2) treatment induced cellular senescence and down-regulated the expression of MEF2A and PI3K/p-AKT/SIRT1. MEF2A overexpression inhibited cellular senescence and the down-regulation of PI3K/p-AKT/SIRT1 induced by H2O2. Further study revealed that MEF2A directly up-regulated the expression of PIK3CA and PIK3CG through MEF2 binding sites in the promoter region. Pearson correlation and logistic regression analysis showed that the plasma level of MEF2A was negatively correlated with CAD, and with age in the controls. These results suggested that MEF2A can directly up-regulate PI3K gene expression, and one of the molecular mechanisms of delaying effect of MEF2A on VEC cell senescence was SIRT1-expression activation through the PI3K/p-Akt pathway. Moreover, the plasma MEF2A levels may be a potential biomarker for CAD risk prediction.

Highlights

Myocyte enhancer factor 2 (MEF2) family shares a 58amino acid homology domain that benefits DNA binding and dimerization
The inhibition of Myocyte enhancer factor 2A (MEF2A) expression in human umbilical-vein endothelial cells (HUVECs) significantly reduced cell viability (Figure 1C), whereas MEF2A overexpression in HUVECs significantly increased cell viability (Figure 1D). These results indicated that the inhibition of MEF2A expression reduced cell viability and enhanced the cellular aging phenotype of HUVECs, whereas MEF2A overexpression increased cell viability and reduced cellular-senescence phenotype
We reported for the first time that MEF2A directly upregulated the expression of PI3K (PIK3CA and PIK3CG) and activated its downstream signaling pathway

Summary

Introduction

Myocyte enhancer factor 2 (MEF2) family shares a 58amino acid homology domain that benefits DNA binding and dimerization. MEF2 belongs to the MADS-box super family and is a class of key transcriptional regulators that positively regulate cell differentiation, cell proliferation, morphogenesis, cell survival, and apoptosis [1, 2]. MEF2A is one of the members of the MEF2 family and participates in various cellular processes, including muscle development, neuronal differentiation, cell-growth control, and apoptosis, in the form of homodimers or heterodimers [3]. As a very important transcription factor, MEF2A has an essential DNA-binding site in the MyoDa www.aging-us.com gene-control region and can activate many musclespecific, growth factor-induced, and stress-induced genes [4, 5]. A comprehensive analysis of target genes for MEF2 in cardiac and skeletal muscles has revealed that MEF2A is involved in the regulation of growth and proliferation gene networks in addition to regulating gene networks involved in muscle development [8]

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Conclusion