Resveratrol attenuates cardiac fibrosis after myocardial infarction by inhibiting endothelial‐to‐mesenchymal transition via regulating the AMPK-mediated TGF-β/Smad signalling pathway

Purpose Endothelial-to‐mesenchymal transition (EndMT) contributes to the progress of cardiac fibrosis in myocardial infarction (MI), which results in cardiac remodelling and deterioration of cardiac function. Resveratrol (RSV), a polyphenol phytoalexin, is present in a variety of plant species and demonstrates cardio-protective effects. Here, we investigated the mechanisms of RSV in protecting the heart against ischaemic injury and reversing cardiac remodelling and dysfunction by inhibiting EndMT progression. Methods Cardiac fibrosis was induced in C57BL/6J mice by ligating left anterior descending (LAD) coronary artery. Experimental animals were treated with RSV or normal saline by oral gavage throughout the study with sham and MI surgery. After surgery 4 weeks, mouse hearts were harvested for histopathological (including Masson and H & E staining, immunohistochemistry, and immunofluorescence) and molecular analysis by western blotting. In addition, cardiac microvascular endothelial cells were used for cellular experiments. Results We found RSV-treatment by oral gavage exerted the anti-fibrotic and cardio-protective effects after MI. Moreover, treatment of RSV resulted in inhibition of EndMT after MI as shown by increased expression of VE-cadherin and CD31, and decreased expression of α-SMA. Then, we performed hypoxic treatment to induce EndMT in vitro to to mimic the pathogenesis of myocardial fibrosis after MI. Consistent with the results obtained in vivo , RSV could also attenuate the EndMT caused by hypoxia. Mechanistically, we performed TGF-β1 and Compound C treatment to demonstrated that RSV inhibited EndMT induced by MI and hypxoia via promoting the phosphorylation of AMPK and subsequently inhibiting the activation of Smad 2/3, thereby improving cardiac function and attenuating cardiac fibrosis. Conclusion RSV attenuated MI- or hypoxia- induced EndMT to delay the progression of cardiac fibrosis mainly through the AMPK-mediated TGF-β/Smad signalling pathway and might be a promising bioactive compound for the treatment and prevention of cardiac fibrosis after MI injury.