Myocyte Enhancer Factor 2A Gene Research Articles

A Study of transcription factor MEF2A gene polymorphisms in patients with coronary artery disease.

MEF2A (myocyte enhancer factor-2A) is a transcription factor of the MEF2 family. It has been recognized as the cause of coronary artery disease in the absence of any other clinical characteristic. It is involved in vascular development and is most commonly found in the coronary artery endothelium. The goal of this case-control study was to see if there was a link between polymorphisms in the MEF2A gene and coronary artery disease. A case-control study was carried out to look into the possible significance of MEF2A polymorphisms as a risk factor for coronary artery disease. This research included 225 patients and 225 healthy controls. A biochemical examination was carried out to evaluate the risk factors for developing this condition. The polymorphisms of Mef2A (1250 C > T in exon 8 and 452 G > T, 481 A > G in exon 11) were found using the PCR-RFLP technique. All identified risk variables, such as hypercholesterolemia, diabetes mellitus, and hypertriglyceridemia, were shown to be statistically significant in the current study for coronary artery disease occurrence. The most polymorphisms were found in MEF2A 1250 C > T, MEF2A 452 G > T, and MEF2A 481 A > G. The genotyping results for MEF2A 1250, MEF2A 452, and MEF2A 481 were (X2 = 2.985; P = 0.235), (X2 = 4.371; P = 0.112), and (X2 = 4.025; P = 0.134), respectively. In conclusion, we identified a much higher incidence of MEF2A in people with coronary artery disease, and MEF2A may play a crucial role in cardiovascular pathophysiology. Patients and controls had considerably different genetics and frequency of alleles.

Effect of Bovine MEF2A Gene Expression on Proliferation and Apoptosis of Myoblast Cells.

Myocyte enhancer factor 2A (MEF2A) is a member of the myocyte enhancer factor 2 family. MEF2A is widely distributed in various tissues and organs and participates in various physiological processes. This study aimed to investigate the effect of MEF2A expression on the proliferation and apoptosis of bovine myoblasts. CCK8, ELISA, cell cycle, and apoptosis analyses were conducted to assess cell status. In addition, the mRNA expression levels of genes associated with bovine myoblast proliferation and apoptosis were evaluated using RT-qPCR. The results showed that the upregulation of MEF2A mRNA promoted the proliferation rate of myoblasts, shortened the cycle process, and increased the anti-apoptotic rate. Furthermore, the RT-qPCR results showed that the upregulation of MEF2A mRNA significantly increased the cell proliferation factors MyoD1 and IGF1, cell cycle factors CDK2 and CCNA2, and the apoptotic factors Bcl2 and BAD (p < 0.01). These results show that the MEF2A gene can positively regulate myoblast proliferation and anti-apoptosis, providing a basis for the analysis of the regulatory mechanism of the MEF2A gene on bovine growth and development.

Variants in MEF2A gene in relation with coronary artery disease in Saudi population.

This study investigated the association of variants in myocyte enhancer factor 2A (MEF2A) gene with coronary artery disease (CAD) via case control study on Saudi population. Several studies have indicated a high expression of MEF2A in the human coronary endothelium. The entire (exon 11 putative susceptibility exon) of MEF2A gene was sequenced using direct DNA sequencing method in 120 sporadic patients and 100 controls. Total number of variants were identified and crude odds ratio (OR) with 95% confidence interval (CI) was calculated. In total, three variants were identified, namely, CAG repeats, AGC deletion, and SNP rs: 325400. No significant link was observed between the common (CAG) n polymorphism, AGC deletion, and CAD risk as reported in other populations, but interestingly, rs325400 (G1323T) in Saudis was found to be associated with the CAD with odds ratio 2.0102 (CI = 1.3405-3.0146) and significance of p = 0.00048. None of Saudi subjects (normal as well as diseased) showed 21-bp deletion as reported previously for other populations. In addition, genotype TT of rs325400 is associated with significantly higher levels of LDL-C and lower level of HDL-C. Among the quantitative parameters, lower HDL-C and higher LDL-C was found to be associated with disease. We report that MEF2A gene based on SNP rs325400 (G1323T) can be considered as a susceptibility factor for CAD and presence of T allele makes Saudis at more risk to CAD, while other variants detected in this gene do not have any association in Saudi population.

Inhibition of myocyte-specific enhancer factor 2A improved diabetic cardiac fibrosis partially by regulating endothelial-to-mesenchymal transition.

Cardiac fibrosis is an important pathological process of diabetic cardiomyopathy, the underlying mechanism remains elusive. This study sought to identify whether inhibition of Myocyte enhancer factor 2A (MEF2A) alleviates cardiac fibrosis by partially regulating Endothelial-to-mesenchymal transition (EndMT). We induced type 1 diabetes mellitus using the toxin streptozotocin (STZ) in mice and injected with lentivirus-mediated short-hairpin RNA (shRNA) in myocardium to inhibit MEF2A expression. Protein expression, histological and functional parameters were examined twenty-one weeks post-STZ injection. We found that Diabetes mellitus increased cardiac MEF2A expression, aggravated cardiac dysfunction and myocardial fibrosis through the accumulation of fibroblasts via EndMT. All of these features were abolished by MEF2A inhibition. MEF2A gene silencing by shRNA in cultured human umbilical vein endothelial cells (HUVECs) ameliorated high glucose–induced phenotypic transition and acquisition of mesenchymal markers through interaction with p38MAPK and Smad2. We conclude that inhibition of endothelial cell-derived MEF2A might be beneficial in the prevention of diabetes mellitus-induced cardiac fibrosis by partially inhibiting EndMT through interaction with p38MAPK and Smad2.

Association of MEF2A gene 3'UTR mutations with coronary artery disease.

Association of variants in the myocyte enhancer factor 2A (MEF2A) gene and the risk of coronary artery disease (CAD) has drawn much attention but remains controversial. We hypothesized that the 3'-untranslated region (3'-UTR) of this gene could harbor functionally relevant nucleotide changes. Here, we assessed the association between single nucleotide polymorphisms (SNPs) in the 3'-UTR of MEF2A and CAD in the Chinese Han population. A case-control study of 236 CAD patients and 278 controls was carried out. The four target SNPs were genotyped using a multiplex PCR-ligase detection reaction method. Logistic regression under three genetic models was used to analyze the association between target SNPs and the risk of CAD. Associations were detected between two SNPs (rs325380, rs897074) and CAD; however, after Bonferroni's correction, these associations were not deemed significant. A further haplotype study indicated that a 'TA' haplotype carrier of rs325380-rs325381 was associated with CAD risk. Our study thus indicates that variants in the 3'-UTR of MEF2A are associated with CAD in a Chinese Han population.

MEF2A gene mutations and susceptibility to coronary artery disease in the Chinese population.

We investigated mutations and polymorphisms of the coronary artery disease (CAD)-related myocyte enhancer factor 2A (MEF2A) gene in a Chinese population. Polymerase chain reaction-single-strand conformation polymorphism and DNA sequencing were used to detect exon 11 of the MEF2A gene in 210 Hubei patients with CAD and 190 healthy controls. The following mutations were identified: a) a synonymous heterozygous mutation (147191G→T) combined with a 6-base deletion (147123-147128); b) a synonymous heterozygous or homozygous mutation (147191G→T) combined with a 9-base deletion (147123-147131); c) a synonymous mutation (147143G→A); d) a synonymous mutation (147191G→T) combined with an 18-base deletion (147111-147128); and e) a 21-base deletion (147108-147128). Mutations (a) and (b) and a 3-base deletion (147126-147128) with or without the synonymous heterozygous mutation (147191G→T) occurred in more than 1% of controls. However, mutations (c), (d), and (e) were not observed in the control group. The polymorphism in exon 11 of the MEF2A gene was observed in the Chinese population. Six or seven amino acid deletions and synonymous mutations (147143G→A) may be correlated with susceptibility to CAD.

Analysis of MEF2A Mutations in a Chinese Population with Premature Coronary Artery Disease

To assess the relationship between mutations of the myocyte enhancer factor 2A (MEF2A) and premature coronary artery disease (PCAD) in a Chinese population. The mutations in the exons 8 and 12 of the MEF2A gene were analyzed in both PCAD families and sporadic cases using direct sequencing of polymerase chain reaction products. In one PCAD family, seven members of the third generation were all diagnosed with CAD, and five of them had PCAD. All five members with PCAD displayed a mutation of the TT genotype in the site of 1353 G/T. Moreover, three of them (3/5) had a mutation of the DW genotype in the site of 1291-1293 CCG W/D. In sporadic cases, we also found that the haplotype of 1291-1293 CCG D+1305 G+1353 T was significantly associated with PCAD. The mutations of MEF2A exon 12 are implicated in PCAD, suggesting a strong genetic component in the pathogenesis of PCAD in the Chinese population.

Variants in Exon 11 of MEF2A Gene and Coronary Artery Disease: Evidence from a Case-Control Study, Systematic Review, and Meta-Analysis

BackgroundCoronary artery disease (CAD) is the most common heart disease worldwide. Association of CAD with variants in the myocyte enhancer factor 2A (MEF2A) gene, the first identified CAD-causing gene, has attracted special attention but the results are controversial. We aimed to evaluate this genetic association via a case-control study and meta-analysis.Methodology/Principal FindingsWe performed a case-control association study to investigate the relationship between variations in exon 11 of MEF2A gene and CAD in 1045 sporadic patients and 1008 controls enrolled angiographically among southern Chinese population, and then the data from this study were compared and discussed in a systematic review and meta-analysis with all available published studies on MEF2A gene and CAD. In total, eight variants were identified (21-bp deletion, CAG repeats, CCG repeats, a CCA deletion and four SNPs). No significant link was observed between the common (CAG)n polymorphism and CAD, whereas the rare 21-bp deletion was detected only in five affected individuals. The meta-analysis of (CAG)n polymorphism and CAD risk, including nine studies with 3801 CAD patients and 4020 controls, also provided no convincing evidence for the genetic association, even upon stratification by race (mainly Whites and Chinese). However, the 21-bp deletion was regarded as a potentially logical, albeit undetermined, candidate for CAD in the following systematic review.Conclusions/SignificanceOur findings failed to demonstrate a correlation between (CAG)n polymorphism with CAD, however, we concluded that the rare 21-bp deletion might have a more compelling effect on CAD than the common (CAG)n polymorphism, and MEF2A genetic variant might be a rare but specific cause of CAD/MI.

Promoter Variant-Dependent mRNA Expression of theMEF2AinLongissimus DorsiMuscle in Cattle

The myocyte enhancer factor 2A (MEF2A) gene encodes a member of the myocyte enhancer factor 2 (MEF2) protein family that is involved in vertebrate skeletal, cardiac, and smooth muscle development and differentiation during myogenesis. According to recent studies, MEF2 genes might be major regulators of postnatal skeletal muscle growth; thus, they are considered to be important, novel candidates for muscle development and body growth in farm animals. The aim of the present study was to search for polymorphisms in the bovine MEF2A gene and analyze their effect on the MEF2A mRNA expression level in the longissimus dorsi muscle of Polish Holstein-Fresian cattle. In total, 4094 bp of the whole coding sequence and the promoter region of MEF2A were re-sequenced in 30 animals, resulting in the detection of 6 novel variants as well as one previously reported SNP. Three linked mutations in the promoter region (-780T/G, g.-768T/G, and g.-222A/G) and only two genotypes were identified in two Polish breeds (TTA/TTA and TTA/GGG). Three SNPs in the coding region [g.1599G/A (421aa), g.1626G/A (429aa), and g.1641G/A (434aa)] appeared to be silent substitutions and segregated as two intragene haplotypes: GGG and AAA. Expression analysis showed that the mutations in the promoter region are highly associated with the MEF2A mRNA level in the longissimus dorsi muscle of bulls carrying two different genotypes. The higher MEF2A mRNA level was estimated in the muscle of bulls carrying the TTA/TTA (p<0.01) genotype as compared with those with TTA/GGG. The results obtained suggest that the nucleotide sequence mutation in MEF2A might be useful marker for body growth traits in cattle.

The effects of myocyte enhancer factor 2A gene on the proliferation, migration and phenotype of vascular smooth muscle cells

The genetic basis for the phenotypic switching of vascular smooth muscle cells (VSMCs) is unclear in atherosclerosis. Recent studies showed that the 21-base pair deletion mutation (Δ21) in myocyte enhancer factor 2A (MEF2A) gene could be an inherited marker for coronary artery disease. MEF2A mutation may affect the phenotypic switching of VSMCs. Human aortic VSMCs were used. Four groups of VSMCs transfected with green fluorescent protein plasmid (control group), MEF2A wild-type (WT) plasmid (WT group), MEF2A Δ21 plasmid (Δ21 group) or MEF2A siRNA (siRNA group) were studied. The proliferation of VSMCs was determined by methylthiazolyldiphenyl-tetrazolium bromide, and the migration of VSMCs was measured by Millicell chamber. The protein expressions of MEF2A, smooth muscle α-actin, SM22α, osteopontin and p38 mitogen-activated protein kinase signaling pathway were detected by Western blotting. MEF2A protein expression was knockdown by siRNA transfection. MEF2A protein was overexpressed in WT and Δ21 groups. Δ21 and siRNA groups obviously showed more proliferation (methylthiazolyldiphenyl-tetrazolium bromide, 0.63 vs 0.66 vs 0.31, P < 0.01) and migration (52.6 vs 58.0 vs 21.2, P < 0.01) of VSMCs as compared with the WT group. In addition, the transfection of Δ21 and siRNA could induce the down-regulation of smooth muscle α-actin and SM22α (P < 0.01) and the up-regulation of osteopontin (P < 0.01) in VSMCs. The phosphorylated p38 signaling pathway expression was significantly enhanced in the Δ21 and siRNA groups as compared with that of the WT group (P < 0.01). These results suggest that MEF2A dominant negative mutation and RNA silence could induce the phenotypic switching of VSMCs, leading to its increased proliferation and migration, and p38 mitogen-activated protein kinase signaling pathway may participate in it.

Structural changes in exon 11 of MEF2A are not related to sporadic coronary artery disease in Han Chinese population

A mutation in MEF2A (myocyte enhancer factor-2A) had been reported to be the first gene linked directly to coronary artery disease (CAD). However, an opposing opinion was proposed recently that MEF2A mutations are not a common cause of sporadic CAD. In this study, we screened exon 11 of the MEF2A gene in people of the Han nationality in China and finished some functional analysis of found variations. A gene structural investigation of MEF2A in 257 CAD patients and 154 control individuals were developed in this study. Subsequently, typical MEF2A variations were cloned and expressed in HeLa or 293T cell line to illustrate whether found structure changes could influence the main biological functions of these proteins. At last, another set of gene structural screen was initialized to get more reliable conclusions. Totally 16 different variations were detected in exon 11 of this gene in the first set of gene structural screen. By cloning and expressing typical MEF2A proteins in cultured cells, all the acquired MEF2A variations had transcriptional activation capabilities and subcellular localization patterns similar to those of the wild-type protein. Further larger scale genetic screening also revealed that the reported genetic variations of MEF2A did not differ significantly between CAD patients and healthy controls. Our results reveal that structural changes of exon 11 in MEF2A are not involved in sporadic CAD in the Han population of China.

Mutation analysis of the myocyte enhancer factor 2A gene (MEF2A) in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy

Mutation analysis of the myocyte enhancer factor 2A gene (<i>MEF2A</i>) in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy

CAG Repeat Polymorphism of the MEF2A Gene is not Associated With the Risk of Coronary Artery Disease Among Taiwanese

A 21-bp deletion mutation of the exon 11 of the myocyte enhancer factor-2A (MEF2A) gene was shown to cause familial coronary artery disease. This finding raises the possibility that MEF2A variants may contribute to the risk of coronary artery disease. In total, 258 patients with coronary artery disease and 258 controls were analyzed for the MEF2A variants. The analysis revealed that all patients were negative for Pro279Leu and 21-bp deletion mutations in exons 7 and 11, respectively. The distribution of the allele frequencies of MEF2A exon 11 CAG repeat (CAG)n polymorphism was similar in both patients and controls; Further, no significant association was noted between MEF2A exon 11 (CAG)n polymorphism and the risk of myocardial infarction. Our data suggest that there is no evidence of an association between the MEF2A exon 11 (CAG)n polymorphism and the risk of coronary artery disease/myocardial infarction in the Chinese population in Taiwan.

Relationship of the CAG repeat polymorphism of the MEF2A gene and coronary artery disease in a Chinese population

Recently, a mutation in the human myocyte enhancer factor-2A (MEF2A) gene was reported to be responsible for an autosomal dominant form of coronary artery disease (CAD). In addition, missense mutations in sporadic CAD patients were also described. Both results support the disease-causing relationship between MEF2A and CAD/myocardial infarction. On the other hand, conflicting hypotheses have been put forward in other studies. We screened exons 7 and 11 of MEF2A through single-stranded conformation polymorphism PCR and direct sequencing to clarify the relationship between MEF2A and CAD in an independent case-control study involving 726 individuals in China. Exon 11 showed a high degree of heterogeneity, which was caused by a polyglutamine (CAG)n polymorphism. Frequencies for the different (CAG)n alleles were not the same between patient and control groups. Of note, the distribution frequency of the (CAG)9 allele was higher in the patient group than in the control group (p<0.001). This effect was independent of age, gender, hypertension, diabetes mellitus, hyperlipidemia and smoking in a logistic regression model (p=0.001, odds ratio 1.245, 95% CI 1.095-1.417). It was also observed that the (CAG)9 allele was related to the extent of CAD, which was defined as no CAD, or single-, double- or triple-vessel disease (p trend 0.000). Based on our data, we speculate that the CAG repeat polymorphism is associated with coronary heart disease in the Chinese population and the (CAG)9 allele may be an independent predictive factor for CAD.