Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy.
Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy.
复制标题
基因敲除通过抑制自噬介导的内皮细胞向间质细胞转化（EndMT）来抑制心脏纤维化。
DOI：
10.1038/s41419-021-03750-4
复制
发表时间：
2021-05-11
影响因子：
9
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Zhang L;He J;Wang J;Liu J;Chen Z;Deng B;Wei L;Wu H;Liang B;Li H;Huang Y;Lu L;Yang Z;Xian S;Wang L
内皮-间充质转化(EndMT)已被证明与心脏纤维化和心力衰竭(HF)有关。最近的研究表明，EndMT是由自噬调节的，我们之前的研究表明，使用晚期糖基化终产物受体(RAGE)失活的心衰小鼠，可以抑制过度的自噬，减轻心肌纤维化。因此，我们调查了RAGE基因敲除是否通过抑制过度自噬介导的EndMT来减少RAGE基因敲除导致的心肌纤维化。8周时，小鼠心脏组织内皮细胞(CD31+/VE-Caherin+)减少，CD31和α-平滑肌肌动蛋白(α-SMA)共表达细胞增多，提示EndMT的存在。基因敲除RAGE降低了EndMT，同时降低了自噬相关蛋白(LC3BII/I和Beclin 1)的表达，减轻了TAC小鼠的心肌纤维化，改善了心功能。此外，3-甲基腺嘌呤(3-MA)和氯喹(CQ)是自噬、减轻EndMT和TAC小鼠心脏纤维化的抑制剂。重要的是，AGEs诱导的EndMT在体内和体外均可被自噬抑制剂阻断。这些结果提示，AGEs/RAGE-自噬-EndMT轴参与了心肌纤维化的发生和敲除RAGE，通过减少自噬调节的EndMT来改善心肌纤维化，这可能是一种有前途的治疗心力衰竭的策略。
Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to cardiac fibrosis and heart failure (HF). Recent studies have demonstrated that EndMT is regulated by autophagy, and we previously showed suppression of excessive autophagy and alleviation of cardiac fibrosis in HF mice with inactivated receptor for advanced glycation end products (RAGE). Thus, we investigated whether reduced cardiac fibrosis due to RAGE knockout occurred by inhibiting EndMT mediated by excessive autophagy. We found a decrease in endothelial cells (CD31+/VE-Cadherin+) and an increase in cells co-expressing CD31 and α-smooth muscle actin (α-SMA, myofibroblast marker) at 8 weeks in heart tissue of mice subjected to transverse aortic constriction (TAC), which implied EndMT. Knockout RAGE decreased EndMT accompanied by decreased expression of autophagy-related proteins (LC3BII/I and Beclin 1), and alleviated cardiac fibrosis and improved cardiac function in TAC mice. Moreover, 3-methyladenine (3-MA) and chloroquine (CQ), inhibitors of autophagy, attenuated EndMT, and cardiac fibrosis in TAC mice. Importantly, EndMT induced by AGEs could be blocked by autophagy inhibitor in vivo and in vitro. These results suggested that AGEs/RAGE-autophagy-EndMT axis involved in the development of cardiac fibrosis and knockout RAGE ameliorated cardiac fibrosis through decreasing EndMT regulated by autophagy, which could be a promising therapeutic strategy for HF.
登录
查看更多内容
影响因子：
20.1
作者：
Gustafsson AB;Gottlieb RA
通讯作者：
Gottlieb RA
影响因子：
9.3
作者：
Hou X;Hu Z;Xu H;Xu J;Zhang S;Zhong Y;He X;Wang N
通讯作者：
Wang N
治疗心力衰竭的简化草药配方：功效、生物活性成分和机制
影响因子：
9.3
作者：
Chen, Zixin;Luo, Tong;Xiang, Shaoxiang
通讯作者：
Xiang, Shaoxiang
影响因子：
37.8
作者：
Kovacic JC;Mercader N;Torres M;Boehm M;Fuster V
通讯作者：
Fuster V
影响因子：
4.8
作者：
Meng, Hong-Zheng;Zhang, Wei-Lin;Yang, Mao-Wei
通讯作者：
Yang, Mao-Wei