Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition mediated by autophagy
Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition mediated by autophagy
复制标题
敲除 RAGE 通过抑制自噬介导的内皮间质转化减轻心脏纤维化
作者：
Zhang Lu;He Jiaqi;Wang Junyan;Liu Jing;Chen Zixin;Deng Bo;Lan Wei;Wu Hanqin;Liang Birong;Li Huan;Huang Yusheng;Lu Lu;Yang Zhongqi;Xian Shaoxiang;Wang Lingjun
内皮-间质转化（EndMT）已被证明有助于心脏纤维化和心力衰竭（HF）。最近的研究表明，EndMT是由自噬调节，我们以前显示过抑制过度自噬和减轻心脏纤维化的HF小鼠与失活的受体为晚期糖基化终产物（EHF）。因此，我们研究了是否通过抑制由过度自噬介导的EndMT来减少由于β-内酰胺酶敲除引起的心脏纤维化。我们发现，在经受横向主动脉缩窄（TAC）的小鼠的心脏组织中，8周时内皮细胞（CD 31 +/VE-Cadherin+）减少，共表达CD 31和α-平滑肌肌动蛋白（α-SMA，肌成纤维细胞标志物）的细胞增加，这暗示了EndMT。在TAC小鼠中，敲除NMT减少EndMT伴随自噬相关蛋白（LC 3BII/I和Beclin 1）的表达减少，减轻心脏纤维化并改善心脏功能。此外，自噬抑制剂3-甲基腺嘌呤（3-MA）和氯喹（CQ）可减轻TAC小鼠的EndMT和心脏纤维化。重要的是，AGEs在体内和体外诱导的EndMT可被自噬抑制剂阻断。提示AGEs/RAGE-autophagy-EndMT轴参与了心脏纤维化的发生发展，Knockout可通过降低由自噬调节的EndMT来减轻心脏纤维化，这可能是一种有前景的治疗心衰的策略。
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, AGEs induced EndMT in vivo and in vitro could be blocked by autophagy inhibitor. 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.