Lack of bcr and abr promotes hypoxia-induced pulmonary hypertension in mice.
Lack of bcr and abr promotes hypoxia-induced pulmonary hypertension in mice.
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DOI：
10.1371/journal.pone.0049756
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Heisterkamp N
中科院分区：
文献类型：
--
作者：
Yu M;Gong D;Lim M;Arutyunyan A;Groffen J;Heisterkamp N
Bcr 和 Abr 是 GTP 酶激活蛋白，可特异性下调体内受限细胞类型中小 GTP 酶 Rac 的活性。 Rac1 在平滑肌细胞中表达，平滑肌细胞是参与肺动脉高压发病机制的关键细胞类型。缺氧相关肺动脉高压的分子机制尚不明确。 将 Bcr 和 abr 缺失突变小鼠与野生型对照小鼠进行比较，以了解暴露于缺氧后肺动脉高压的发生情况。此外，在缺氧条件下培养这些小鼠的肺动脉平滑肌细胞，并检查其增殖、p38 激活和 IL-6 的产生。缺乏 Bcr 或 Abr 的小鼠暴露在缺氧环境中会出现右心室压力升高、肥大和肺血管重塑。肺部血管周围白细胞浸润增加，缺氧时 bcr−/− 和 abr−/− 巨噬细胞产生更多活性氧。与炎症和氧化应激在肺动脉高压相关血管损伤中的作用一致，Bcr 和 Abr 缺陷的动物在缺氧暴露后表现出内皮渗漏增加。来自 Bcr 或 Abr 缺陷小鼠的缺氧处理的肺动脉平滑肌细胞也比野生型小鼠增殖得更快。此外，在缺乏 Bcr 或 Abr 的情况下，这些细胞中活化的 Rac1、磷酸化 p38 和白细胞介素 6 均增加。使用新型 Rac 抑制剂 Z62954982 抑制 Rac1 激活，可降低暴露于缺氧的肺动脉平滑肌细胞的增殖、p38 磷酸化和 IL-6 水平。 Bcr 和 Abr 通过使 Rac1 失活，在下调缺氧诱导的肺动脉高压中发挥关键作用，从而减少白细胞产生的氧化应激以及 p38 磷酸化、IL-6 的产生和肺动脉平滑肌细胞的增殖。
Bcr and Abr are GTPase activating proteins that specifically downregulate activity of the small GTPase Rac in restricted cell types in vivo. Rac1 is expressed in smooth muscle cells, a critical cell type involved in the pathogenesis of pulmonary hypertension. The molecular mechanisms that underlie hypoxia-associated pulmonary hypertension are not well-defined. Bcr and abr null mutant mice were compared to wild type controls for the development of pulmonary hypertension after exposure to hypoxia. Also, pulmonary arterial smooth muscle cells from those mice were cultured in hypoxia and examined for proliferation, p38 activation and IL-6 production. Mice lacking Bcr or Abr exposed to hypoxia developed increased right ventricular pressure, hypertrophy and pulmonary vascular remodeling. Perivascular leukocyte infiltration in the lungs was increased, and under hypoxia bcr−/− and abr−/− macrophages generated more reactive oxygen species. Consistent with a contribution of inflammation and oxidative stress in pulmonary hypertension-associated vascular damage, Bcr and Abr-deficient animals showed elevated endothelial leakage after hypoxia exposure. Hypoxia-treated pulmonary arterial smooth muscle cells from Bcr- or Abr-deficient mice also proliferated faster than those of wild type mice. Moreover, activated Rac1, phosphorylated p38 and interleukin 6 were increased in these cells in the absence of Bcr or Abr. Inhibition of Rac1 activation with Z62954982, a novel Rac inhibitor, decreased proliferation, p38 phosphorylation and IL-6 levels in pulmonary arterial smooth muscle cells exposed to hypoxia. Bcr and Abr play a critical role in down-regulating hypoxia-induced pulmonary hypertension by deactivating Rac1 and, through this, reducing both oxidative stress generated by leukocytes as well as p38 phosphorylation, IL-6 production and proliferation of pulmonary arterial smooth muscle cells.
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