Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats.
Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats.
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DOI：
10.1186/s12890-018-0700-y
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发表时间：
2018-08-07
影响因子：
3.1
通讯作者：
Xie W
中科院分区：
文献类型：
--
作者：
Cheng Y;Yu M;Xu J;He M;Wang H;Kong H;Xie W
含有蛋白酪氨酸磷酸酶（PTP）2（Shp2）的Src同源2是一种典型的酪氨酸磷酸酶，与受体酪氨酸激酶相互作用，调节多种病理过程中的多种信号通路。在这里，我们将在大鼠模型中研究 Shp2 抑制对肺动脉高压 (PAH) 的影响及其潜在的细胞和分子机制。本研究使用野百合碱 (MCT) 诱导的 PAH 大鼠模型。 Phps-1 是一种 Shp2 的高选择性抑制剂，在 MCT 单次注射后 21 天至 35 天进行注射。采用微导管法检测血流动力学参数。采用组织学方法测定 PAH 大鼠的 PVR 变化。此外，培养的肺动脉平滑肌细胞（PASMC）经过血小板衍生生长因子（PDGF）处理（有或没有Phps-1），用于研究体外潜在的细胞和分子机制。抑制Shp2可显着减弱MCT引起的大鼠平均肺动脉压(mPAP)、右心室收缩压(RVSP)和右心室肥厚(RVH)的增加。在 MCT 治疗的大鼠中，Shp2 抑制可有效减少肺动脉中膜增厚和心肌细胞肥大以及血管周围和心肌纤维化。此外，Shp2 抑制可改善 MCT 诱导的 PAH 大鼠肺小动脉的肌化。 Shp2 抑制显着降低血小板源性生长因子 (PDGF) 触发的人肺动脉平滑肌细胞 (PASMC) 的增殖和迁移，这可能归因于 Akt 和 Stat3 通路的失活。 Shp2 有助于大鼠 PAH 的发生，这可能是治疗 PAH 的潜在靶点。
Src homology 2 containing protein tyrosine phosphatase (PTP) 2 (Shp2) is a typical tyrosine phosphatase interacting with receptor tyrosine kinase to regulate multiple signaling pathways in diverse pathological processes. Here, we will investigate the effect of Shp2 inhibition on pulmonary arterial hypertension (PAH) in a rat model and its potential cellular and molecular mechanisms underlying. Monocrotaline (MCT)-induced PAH rat model was used in this study. Phps-1, a highly selective inhibitor for Shp2, was administered from 21 days to 35 days after MCT single-injection. Microcatheter method was applied to detected hemodynamic parameters. Histological methods were used to determine PVR changes in PAH rats. Moreover, cultured pulmonary artery smooth muscle cells (PASMCs) treated by platelet-derived growth factor (PDGF) with or without Phps-1 was used to investigate the potential cellular and molecular mechanisms underlying in vitro. Inhibition of Shp2 significantly attenuated MCT-induced increases of mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in rats. Shp2 inhibition effectively decreased thickening of pulmonary artery media and cardiomyocyte hypertrophy as well as perivascular and myocardial fibrosis in MCT-treated rats. Moreover, Shp2 inhibition ameliorated muscularization of pulmonary arterioles in MCT-induced PAH rats. Shp2 inhibition significantly reduced platelet-derived growth factor (PDGF)-triggered proliferation and migration of human pulmonary artery smooth muscle cells (PASMCs), which might be attributed to the inactivations of Akt and Stat3 pathways. Shp2 contributes to the development of PAH in rats, which might be a potential target for the treatment of PAH.
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影响因子：
8
作者：
Sausgruber, N.;Coissieux, M-M;Bentires-Alj, M.
通讯作者：
Bentires-Alj, M.
DOI：
10.1152/ajpheart.00329.2013
发表时间：
2013-11-01
影响因子：
4.8
作者：
Pankey, Edward A.;Thammasiboon, Supat;Kadowitz, Philip J.
通讯作者：
Kadowitz, Philip J.
影响因子：
37.8
作者：
Hadri L;Kratlian RG;Benard L;Maron BA;Dorfmüller P;Ladage D;Guignabert C;Ishikawa K;Aguero J;Ibanez B;Turnbull IC;Kohlbrenner E;Liang L;Zsebo K;Humbert M;Hulot JS;Kawase Y;Hajjar RJ;Leopold JA
通讯作者：
Leopold JA
RPL22 siRNA对ET-1诱导的人肺动脉平滑肌细胞增殖的影响
影响因子：
5.4
作者：
Sun, Kai;Xue, Hong;Wang, Hong
通讯作者：
Wang, Hong
影响因子：
37.8
作者：
Klein, Martina;Schermuly, Ralph T.;Schaefer, Stefan
通讯作者：
Schaefer, Stefan