Ablation of RAGE Attenuated Cardiac Fibrosis by Inhibition of Autophagy medicated Endothelial‐to‐mesenchymal transition

Abstract

Endothelial‐to‐mesenchymal transition (EndMT) has been found involved in the progression of heart failure (HF), which maybe one of the source of myofibroblasts. Emerging evidence support the notion that EndMT was regulated by autophagy. Our previous studies demonstrated deletion of receptor for advanced glycation end products (RAGE) inhibited autophagy and attenuated cardiac fibrosis in HF. Thus, here we investigated whether reduction of cardiac fibrosis by ablation of RAGE was through inhibition autophagy medicated EndMT. Using transverse aortic constriction (TAC) in mice as a model of pressure overload induced HF, we demonstrated that EndMT and autophagy were induced simultaneously at 8 weeks after TAC. Co‐localization of CD31 and α‐smooth muscle actin (α‐SMA) was observed in myocardium. Knockout of RAGE displayed reduced cardiac fibrosis and significantly improved cardiac function in TAC mice. Importantly, knockout of RAGE deceased the expression of autophagy related proteins (LC3BII/I and Beclin1), which was accompanied with the decrease of co‐expression of CD31 and α‐SMA in TAC mouse hearts. Moreover, 3‐methyladenine (3‐MA) and chloroquine (CQ), inhibitors of autophagy, attenuated EndMT and cardiac fibrosis in TAC mice. Taken together autophagy inducing EndMT may contribute to the development of cardiac fibrosis. Inhibition of this process by RAGE deletion lead to cardiac function improvement and reduction of cardiac fibrosis. Thus, we concluded that inhibition of the RAGE‐autophagy‐EndMT axis could be a novel strategy for treatment of heart failure.Support or Funding InformationThe National Natural Science Foundation of China (81373570, 81673920, 81473621, 81673796 and 81973776). The Natural Science Foundation of Guangdong Province(2016A030311030).Reduction of cardiac fibrosis especially cardiovascular fibrosis after TAC by inhibition of RAGE and autophagy (Scale bar= 1,000 μm. n = 4. Values are shown as means ± SEM, *P < 0.05 vs Sham group, #P < 0.05 vs TAC group.)Figure 1Deceased expression of autophagy and EndMT after TAC by inhibition of RAGE and autophagy. (n = 4. Values are shown as means ± SEM, *P < 0.05 vs Sham group, #P < 0.05 vs TAC group.)Figure 2