Vascular smooth muscle ROCK1 contributes to hypoxia-induced pulmonary hypertension development in mice.
Vascular smooth muscle ROCK1 contributes to hypoxia-induced pulmonary hypertension development in mice.
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血管平滑肌ROCK 1参与小鼠缺氧诱导的肺动脉高压的形成
DOI：
10.1016/j.bbrc.2022.02.064
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发表时间：
2022-05-14
影响因子：
3.1
通讯作者：
Toksoz, Deniz
中科院分区：
文献类型：
--
作者：
Penumatsa, Krishna C.;Singhal, Adit A.;Warburton, Rod R.;Bear, Michael D.;Bhedi, Chinmayee D.;Nasirova, Sabina;Wilson, Jamie L.;Qi, Guanming;Preston, Ioana R.;Hill, Nicholas S.;Fanburg, Barry L.;Kim, Young-Bum;Toksoz, Deniz
Rho激酶（ROCK）与肺动脉高压（PAH）的发生有关，肺动脉高压中肺血管平滑肌（VSM）收缩和重塑异常导致右心衰竭。药理学ROCK抑制剂阻断啮齿动物实验性肺动脉高压（PH）的发展，但可能具有脱靶效应，并且不能区分由不同基因编码的两种ROCK形式ROCK1和ROCK2。早期的一项在小鼠中使用基因敲除（KO）的研究表明，VSM ROCK 2是实验性PH发展所必需的，但ROCK 1的作用还不清楚。在这里，我们研究了在PH发展中的ROCK1在体内的作用，通过产生VSM靶向的纯合ROCK1基因KO小鼠品系。暴露于Sugen 5416（Su）/缺氧处理以诱导PH的成年对照小鼠与常氧对照相比，右心室收缩压（RVSP）和RV肥大显著增加。相比之下，Su/缺氧暴露的VSM ROCK 1 KO小鼠没有表现出显着的RVSP升高，RV肥大也被减弱。在对照组和VSM ROCK1 KO动物中，Su/低氧诱导的肺小血管肌化也相似地升高。siRNA介导的ROCK 1敲低（KD）在人PAH肺动脉SM细胞（PASMC）中不影响细胞生长。然而，ROCK1 KD导致阿托伐他汀处理的PAH PASMC中AKT和MYPT1信号转导减少。研究结果表明，与VSM ROCK 2一样，VSM ROCK 1积极促进PH的发展，但与之不同的是，VSM ROCK 1通过非增殖途径促进低氧血症，因此可能是PH的独特治疗靶点。
Rho kinase (ROCK) is implicated in the development of pulmonary arterial hypertension (PAH) in which abnormal pulmonary vascular smooth muscle (VSM) contractility and remodeling lead to right heart failure. Pharmacologic ROCK inhibitors block experimental pulmonary hypertension (PH) development in rodents but can have off-target effects and do not distinguish between the two ROCK forms, ROCK1 and ROCK2, encoded by separate genes. An earlier study using gene knock out (KO) in mice indicated that VSM ROCK2 is required for experimental PH development, but the role of ROCK1 is not well understood. Here we investigated the in vivo role of ROCK1 in PH development by generating a VSM-targeted homozygous ROCK1 gene KO mouse strain. Adult control mice exposed to Sugen5416 (Su)/hypoxia treatment to induce PH had significantly increased right ventricular systolic pressures (RVSP) and RV hypertrophy versus normoxic controls. In contrast, Su/hypoxia-exposed VSM ROCK1 KO mice did not exhibit significant RVSP elevation, and RV hypertrophy was blunted. Su/hypoxia-induced pulmonary small vessel muscularization was similarly elevated in both control and VSM ROCK1 KO animals. siRNA-mediated ROCK1 knock-down (KD) in human PAH pulmonary arterial SM cells (PASMC) did not affect cell growth. However, ROCK1 KD led to reduced AKT and MYPT1 signaling in serotonin-treated PAH PASMC. The findings suggest that like VSM ROCK2, VSM ROCK1 actively contributes to PH development, but in distinction acts via nonproliferative pathways to promote hypoxemia, and thus may be a distinct therapeutic target in PH.
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影响因子：
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作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M
影响因子：
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作者：
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DOI：
10.1164/rccm.200805-691oc
发表时间：
2009-06-15
影响因子：
24.7
作者：
Guilluy, Christophe;Eddahibi, Saadia;Pacaud, Pierre
通讯作者：
Pacaud, Pierre