PM2.5-induced ADRB2 hypermethylation contributed to cardiac dysfunction through cardiomyocytes apoptosis via PI3K/Akt pathway

Background: Long-term exposure to fine particulate matter (PM2.5) can causally contribute to progression of atherosclerosis, risk of ischemic heart disease and death, but the underlying mechanism is little known. Since DNA methylation impacts the process of heart disease, it might be useful in exploring potential mechanistic pathways linking PM2.5 exposure and heart disease. Objectives: Here, we investigated the PM2.5-induced ADRB2 hypermethylation and the involving epigenetic mechanism of PM2.5-induced cardiomyocytes apoptosis and cardiac dysfunction. Methods and results: In vitro, PM2.5 markedly augmented cardiotoxicity including oxidative damage and apoptosis in cardiomyocytes AC16 as well as epigenetic alteration. DNA methylation profiling revealed a significant gene-ADRB2 was involved in the cardiac relative GO and KEGG pathways. Methylation chip and Bisulfite Sequencing PCR (BSP) both identified the hypermethylation status of ADRB2 which encodes beta 2-Adrenergic receptor (beta 2AR). Mechanistic study showed ADRB2 hypermethylation-induced down-regulation of beta 2AR inhibited PI3K/Akt and then activated Bcl-2/BAX and p53 pathway in AC16. The transgenic cell lines showed over-expression of ADRB2 weakened the PM2.5-induced cardiomyocytes apoptosis in opposite way, but was augmented by PI3K inhibitor (LY294002). In vivo, echocardiography showed the heart contractile function was decreased after SD rats intratracheal instillation of PM2.5 for 30 days. The myocardial interstitial edema, myocardial gap expansion and myofibril disorder in PM2.5 treated group were observed in rats heart tissue. What's more, basal expression of beta 2AR and VEGFR2 decreased in heart tissue as the dosage of PM2.5 increasing, meanwhile PM2.5 markedly attenuated PI3K/Akt pathway followed by augmented Bcl-2/BAX and p53 pathway, thus caused a greater number of TUNEL positive cardiomyocytes resulted in cardiac dysfunction in vivo. Conclusions: PM2.5 exposure could cause the myocardial ADRB2 hypermethylation and activate the beta 2AR/PI3K/Akt pathway, resulted in PM2.5-induced cardiomyocytes apoptosis and cardiac dysfunction. Our study suggested that the ADRB2 demethylation or ADRB2/beta 2AR activation may serve as a potential pathway to prevent cardiac dysfunction induced by PM2.5 exposure.