A Critical Role of the mTOR/eIF2α Pathway in Hypoxia-Induced Pulmonary Hypertension.
A Critical Role of the mTOR/eIF2α Pathway in Hypoxia-Induced Pulmonary Hypertension.
复制标题
DOI：
10.1371/journal.pone.0130806
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Li YJ
中科院分区：
文献类型：
--
作者：
Wang AP;Li XH;Yang YM;Li WQ;Zhang W;Hu CP;Zhang Z;Li YJ
肺动脉血管平滑肌细胞(PASMCs)增殖增强是缺氧性肺动脉高压(HPH)血管重构的重要病理成分。哺乳动物靶向雷帕霉素(MTOR)信号已被证明在蛋白质翻译中发挥作用，并参与肺动脉高压的进展。真核细胞翻译起始因子-2α(eIF2α)是调节细胞生长和细胞周期的关键因子，但其在mTOR信号转导和PASMC增殖中的作用尚不清楚。采用低氧法建立大鼠肺动脉高压(PH)模型。用雷帕霉素作为mTOR抑制剂治疗大鼠。用低氧诱导原代培养的大鼠PASMCs增殖，用雷帕霉素、mTOR和eIF2α的小干扰RNA进行功能丧失研究。分析eIF2α、mTOR和c-myc的表达和活化情况。结果表明，低氧大鼠和低氧条件下培养的PASMC均可明显激活mTOR/eIF2α信号通路。MTOR抑制剂治疗21d可减轻高血压大鼠血管重塑，抑制mTOR和eIF2mRNA的激活，抑制c-α的表达。在低氧诱导的PASMC中，雷帕霉素和siRNA下调mTOR和eIF2α可显著抑制细胞增殖，增加c-myc的表达。这些结果提示mTOR/eIF2α通路在HPH缺氧性血管重构和PASMCs增殖中起重要作用。
Enhanced proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is a key pathological component of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Mammalian targeting of rapamycin (mTOR) signaling has been shown to play a role in protein translation and participate in the progression of pulmonary hypertension. Eukaryotic translation initiation factor-2α (eIF2α) is a key factor in regulation of cell growth and cell cycle, but its role in mTOR signaling and PASMCs proliferation remains unknown. Pulmonary hypertension (PH) rat model was established by hypoxia. Rapamycin was used to treat rats as an mTOR inhibitor. Proliferation of primarily cultured rat PASMCs was induced by hypoxia, rapamycin and siRNA of mTOR and eIF2α were used in loss-of-function studies. The expression and activation of eIF2α, mTOR and c-myc were analyzed. Results showed that mTOR/eIF2α signaling was significantly activated in pulmonary arteries from hypoxia exposed rats and PASMCs cultured under hypoxia condition. Treatment with mTOR inhibitor for 21 days attenuated vascular remodeling, suppressed mTOR and eIF2α activation, inhibited c-myc expression in HPH rats. In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression. These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH.
登录
查看更多内容
影响因子：
--
作者：
Eckerdt F;Beauchamp E;Bell J;Iqbal A;Su B;Fukunaga R;Lulla RR;Goldman S;Platanias LC
通讯作者：
Platanias LC
影响因子：
4.2
作者：
Anand, P;Gruppuso, PA
通讯作者：
Gruppuso, PA
影响因子：
4.8
作者：
Moss, Stephanie C.;Lightell, Daniel J., Jr.;Woods, T. Cooper
通讯作者：
Woods, T. Cooper
降钙素基因相关肽对缺氧诱导的大鼠肺动脉平滑肌细胞增殖的抑制作用：ERK1/2和p27的作用
影响因子：
5
作者：
Li, Xian-Wei;Hu, Chang-Ping;Li, Yuan-Jian
通讯作者：
Li, Yuan-Jian
影响因子：
37.8
作者：
Goncharov DA;Kudryashova TV;Ziai H;Ihida-Stansbury K;DeLisser H;Krymskaya VP;Tuder RM;Kawut SM;Goncharova EA
通讯作者：
Goncharova EA