Role of RhoB in the regulation of pulmonary endothelial and smooth muscle cell responses to hypoxia.
Role of RhoB in the regulation of pulmonary endothelial and smooth muscle cell responses to hypoxia.
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DOI：
10.1161/circresaha.112.264473
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发表时间：
2012-05-25
影响因子：
20.1
通讯作者：
Wilkins MR
中科院分区：
文献类型：
--
作者：
Wojciak-Stothard B;Zhao L;Oliver E;Dubois O;Wu Y;Kardassis D;Vasilaki E;Huang M;Mitchell JA;Harrington LS;Prendergast GC;Wilkins MR
RhoA和Rho激酶参与肺动脉高压的肺血管收缩和血管重构。RhoB是一种与RhoA同源的蛋白质，可通过缺氧激活，调节肿瘤生长和血管收缩，但其在肺血管功能调节中的作用尚不清楚。探讨RhoB在慢性缺氧性肺动脉高压肺血管重构中的作用。缺氧可增加人肺动脉内皮细胞和平滑肌细胞RhoB的表达和活性，同时也可激活RhoA。缺氧或腺病毒过度表达组成性激活RhoB增加肌动球蛋白收缩性，诱导内皮通透性，并促进细胞生长;显性负RhoB或manumycin，法尼基转移酶抑制剂，靶向RhoB的血管功能，抑制缺氧的影响。RhoA和RhoB的协同激活最大化了RhoB/果蝇透明诱导的肌动蛋白聚合和RhoA/Rho激酶诱导的肌球蛋白轻链Ser 19磷酸化的哺乳动物同系物引起的缺氧诱导的应力纤维形成。值得注意的是，RhoB是低氧诱导的因子-1 α稳定化以及低氧和血小板衍生生长因子诱导的细胞增殖和迁移所特异性需要的。尽管RhoA在肺中有代偿性表达，但RhoB缺乏可显著减弱慢性缺氧诱导的肺动脉高压的发展。RhoB介导血管系统对急性缺氧的适应性变化，但慢性缺氧对其的持续激活可加重血管重塑，从而促进肺动脉高压的发展。RhoB是一个潜在的新方法（如法尼基转移酶抑制剂），旨在调节肺血管张力和结构的目标。(Circ Res. 2012;110：1423-1434）。
RhoA and Rho kinase contribute to pulmonary vasoconstriction and vascular remodeling in pulmonary hypertension. RhoB, a protein homologous to RhoA and activated by hypoxia, regulates neoplastic growth and vasoconstriction but its role in the regulation of pulmonary vascular function is not known. To determine the role of RhoB in pulmonary endothelial and smooth muscle cell responses to hypoxia and in pulmonary vascular remodeling in chronic hypoxia-induced pulmonary hypertension. Hypoxia increased expression and activity of RhoB in human pulmonary artery endothelial and smooth muscle cells, coincidental with activation of RhoA. Hypoxia or adenoviral overexpression of constitutively activated RhoB increased actomyosin contractility, induced endothelial permeability, and promoted cell growth; dominant negative RhoB or manumycin, a farnesyltransferase inhibitor that targets the vascular function of RhoB, inhibited the effects of hypoxia. Coordinated activation of RhoA and RhoB maximized the hypoxia-induced stress fiber formation caused by RhoB/mammalian homolog of Drosophila diaphanous-induced actin polymerization and RhoA/Rho kinase-induced phosphorylation of myosin light chain on Ser19. Notably, RhoB was specifically required for hypoxia-induced factor-1α stabilization and for hypoxia-and platelet-derived growth factor-induced cell proliferation and migration. RhoB deficiency in mice markedly attenuated development of chronic hypoxia-induced pulmonary hypertension, despite compensatory expression of RhoA in the lung. RhoB mediates adaptational changes to acute hypoxia in the vasculature, but its continual activation by chronic hypoxia can accentuate vascular remodeling to promote development of pulmonary hypertension. RhoB is a potential target for novel approaches (eg, farnesyltransferase inhibitors) aimed at regulating pulmonary vascular tone and structure. (Circ Res. 2012;110:1423–1434.)