Abstract
BackgroundMyocyte enhancer factor 2A (MEF2A) plays an important role in cell proliferation, differentiation and survival. Functional deletion or mutation in MEF2A predisposes individuals to cardiovascular disease mainly caused by vascular endothelial dysfunction. However, the effect of the inhibition of MEF2A expression on human coronary artery endothelial cells (HCAECs) is unclear. In this study, expression of MEF2A was inhibited by specific small interference RNA (siRNA), and changes in mRNA profiles in response to MEF2A knockdown were analyzed using an Agilent human mRNA array.ResultsSilencing of MEF2A in HCAECs accelerated cell senescence and suppressed cell proliferation. Microarray analysis identified 962 differentially expressed genes (DEGs) between the MEF2A knockdown group and the negative control group. Annotation clustering analysis showed that the DEGs were preferentially enriched in gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to proliferation, development, survival, and inflammation. Furthermore, 61 of the 578 downregulated DEGs have at least one potential MEF2A binding site in the proximal promoter and were mostly enriched in the GO terms “reproduction” and “cardiovascular.” The protein–protein interaction network analyzed for the downregulated DEGs and the DEGs in the GO terms “cardiovascular” and “aging” revealed that PIK3CG, IL1B, IL8, and PRKCB were included in hot nodes, and the regulation of the longevity-associated gene PIK3CG by MEF2A has been verified at the protein level, suggesting that PIK3CG might play a key role in MEF2A knockdown induced HCAEC senescence.ConclusionsMEF2A knockdown accelerates HCAEC senescence, and the underlying molecular mechanism may be involved in down-regulation of the genes related with cell proliferation, development, inflammation and survival, in which PIK3CG may play a key role.
Highlights
Myocyte enhancer factor 2A (MEF2A) plays an important role in cell proliferation, differentiation and survival
Inhibition of MEF2A in human coronary artery endothe‐ lial cells (HCAEC) promoted cellular senescence and suppressed proliferation In this study, we attempted to understand the effect of inhibiting the MEF2A expression on HCAECs
MEF2A-1527 had a significant inhibitory effect on MEF2A when it was transfected at different concentrations in HCAEC (Fig. 1b), and a final concentration of 40 nM MEF2A-1527 remarkably inhibited MEF2A at both mRNA (Fig. 1c) and protein (Fig. 1d) levels in HCAEC
Summary
Myocyte enhancer factor 2A (MEF2A) plays an important role in cell proliferation, differentiation and survival. The effect of the inhibition of MEF2A expression on human coronary artery endothelial cells (HCAECs) is unclear. Silencing of MEF2A in a poE−/− mice by using lentiviral shRNA considerably reduces plaque collagen content and fibrous cap thickness and increases plaque area; silencing of MEF2A has no obvious effect on plaque lipid content [19]. These studies have suggested that MEF2A plays important roles in cardiomyocytes, VSMCs, and pulmonary arterial endothelial cells, but its functions in coronary artery endothelial cells are unclear. We described a downstream molecular network controlled by MEF2A
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