Epigallocatechin-3-gallate ameliorates hypoxia-induced pulmonary vascular remodeling by promoting mitofusin-2-mediated mitochondrial fusion
Epigallocatechin-3-gallate ameliorates hypoxia-induced pulmonary vascular remodeling by promoting mitofusin-2-mediated mitochondrial fusion
复制标题
Epigallocatechin-3-gallate 通过促进 mitofusin-2 介导的线粒体融合来改善缺氧诱导的肺血管重塑。
DOI：
10.1016/j.ejphar.2017.05.003
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发表时间：
2017
影响因子：
5
通讯作者：
Hu Chang-Ping
中科院分区：
文献类型：
--
作者：
Zhu Tian-Tian;Zhang Wei-Fang;Luo Ping;He Fang;Ge Xiao-Yue;Zhang Zheng;Hu Chang-Ping
肺动脉高压（PH）主要是由于肺动脉平滑肌细胞（PASMCs）过度增殖，并表现为线粒体断裂等线粒体异常。表没食子儿茶素没食子酸酯（Epigallocatechin-3-gallate，EGCG）是绿色茶中的一种有效的抗增殖化合物，近年来研究表明其对PASMCs增殖有抑制作用。然而，临床前的问题，是否EGCG减弱PH和潜在的机制尚未得到解决。本研究旨在探讨表没食子儿茶素没食子酸酯（EGCG）对肺动脉高压的治疗作用及其对肺动脉平滑肌细胞线粒体断裂的影响。大鼠暴露于缺氧（10%O_2，3周）后出现PH。剂量依赖性地减轻右心室收缩压、肺血管重构和右心室肥大，增加线粒体融合蛋白-线粒体融合蛋白-2（MFN-2）的表达，并促进线粒体融合，如肺动脉PASMCs中线粒体的数量和体积减少所证明的。EGCG（50 μM）通过KLF-4/MFN-2/p-Erk信号通路下调低氧（3%O2，48 h）诱导的PASMCs线粒体碎片化，抑制PASMCs增殖。总的来说，我们的数据表明，EGCG通过调节PASMCs的线粒体片段化而发挥抗增殖作用，并且EGCG有望作为抗PH的药物。
Pulmonary hypertension (PH) mainly results from excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and displays mitochondrial abnormalities such as mitochondrial fragmentation. Epigallocatechin-3-gallate (EGCG), an efficient antiproliferative compound in green tea, has recently been demonstrated to inhibit PASMCs proliferation. However, the pre-clinical issues as to whether EGCG attenuates PH and the underlying mechanisms have yet to be addressed. The present study was undertaken to investigate the therapeutic effects of EGCG on PH and its effects on mitochondrial fragmentation in PASMCs. Rats exposed to hypoxia (10% O2, 3 weeks) developed PH. EGCG (50, 100 or 200 mg/kg/d, i.g.) dose-dependently attenuated right ventricular systolic pressure, pulmonary vascular remodeling and right ventricular hypertrophy, increased expression of mitochondrial fusion protein - mitofusin-2 (MFN-2), and promoted mitochondrial fusion as evidenced by decreased number and volume of mitochondria in PASMCs of pulmonary arteries. Notably, EGCG (50 μM) downregulated hypoxia-induced (3% O2, 48 h) PASMCs mitochondrial fragmentation and inhibited PASMCs proliferation via KLF-4/MFN-2/p-Erk signaling pathway. Collectively, our data demonstrated that EGCG exerts antiproliferative effects via regulating mitochondrial fragmentation of PASMCs and EGCG holds the promise as a drug against PH.