Fagan Karen A, Oka Masahiko, Bauer Natalie R, Gebb Sarah A, Ivy D Dunbar, Morris Kenneth G, McMurtry Ivan F
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L656-64. doi: 10.1152/ajplung.00090.2003. Epub 2004 Feb 20.
RhoA GTPase mediates a variety of cellular responses, including activation of the contractile apparatus, growth, and gene expression. Acute hypoxia activates RhoA and, in turn, its downstream effector, Rho-kinase, and previous studies in rats have suggested a role for Rho/Rho-kinase signaling in both acute and chronically hypoxic pulmonary vasoconstriction. We therefore hypothesized that activation of Rho/Rho-kinase in the pulmonary circulation of mice contributes to acute hypoxic pulmonary vasoconstriction and chronic hypoxia-induced pulmonary hypertension and vascular remodeling. In isolated, salt solution-perfused mouse lungs, acute administration of the Rho-kinase inhibitor Y-27632 (1 x 10(-5) M) attenuated hypoxic vasoconstriction as well as that due to angiotensin II and KCl. Chronic treatment with Y-27632 (30 mg x kg(-1) x day(-1)) via subcutaneous osmotic pump decreased right ventricular systolic pressure, right ventricular hypertrophy, and neomuscularization of the distal pulmonary vasculature in mice exposed to hypobaric hypoxia for 14 days. Analysis of a small number of proximal pulmonary arteries suggested that Y-27632 treatment reduced the level of phospho-CPI-17, a Rho-kinase target, in hypoxic lungs. We also found that endothelial nitric oxide synthase protein in hypoxic lungs was augmented by Y-27632, suggesting that enhanced nitric oxide production might have played a role in the Y-27632-induced attenuation of chronically hypoxic pulmonary hypertension. In conclusion, Rho/Rho-kinase activation is important in the effects of both acute and chronic hypoxia on the pulmonary circulation of mice, possibly by contributing to both vasoconstriction and vascular remodeling.
RhoA GTP酶介导多种细胞反应，包括收缩装置的激活、生长和基因表达。急性缺氧会激活RhoA，进而激活其下游效应器Rho激酶，此前在大鼠中的研究表明Rho/Rho激酶信号在急性和慢性低氧性肺血管收缩中均起作用。因此，我们推测小鼠肺循环中Rho/Rho激酶的激活促成急性低氧性肺血管收缩以及慢性缺氧诱导的肺动脉高压和血管重塑。在分离的、用盐溶液灌注的小鼠肺中，急性给予Rho激酶抑制剂Y-27632（1×10⁻⁵ M）可减弱低氧性血管收缩以及由血管紧张素II和氯化钾引起的血管收缩。通过皮下渗透泵用Y-27632（30 mg·kg⁻¹·天⁻¹）对暴露于低压缺氧14天的小鼠进行慢性治疗，可降低右心室收缩压、右心室肥大以及远端肺血管的新肌化。对少数近端肺动脉的分析表明，Y-27632治疗降低了低氧肺中Rho激酶靶点磷酸化CPI-17的水平。我们还发现，Y-27632可增加低氧肺中内皮型一氧化氮合酶蛋白，这表明一氧化氮生成增加可能在Y-27632诱导的慢性低氧性肺动脉高压减弱中发挥了作用。总之，Rho/Rho激酶激活在急性和慢性缺氧对小鼠肺循环的影响中很重要，可能是通过促成血管收缩和血管重塑来实现的。
