Rho/Rho kinase in hypoxic pulmonary hypertension

Rho/Rho 激酶在缺氧性肺动脉高压中的作用

• 批准号: 7049536
• 负责人: IVAN F MCMURTY
• 金额: $ 23.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7049536
• 关键词: angiogenesis; calcium flux; endothelin; enzyme activity; gene expression; guanine nucleotide binding protein; guanosinetriphosphatases; laboratory rat; nitric oxide; nitric oxide synthase; pathologic process; perfusion; pulmonary artery; pulmonary hypertension; respiratory hypoxia; respiratory pharmacology; serine threonine protein kinase; serotonin; tissue /cell culture; vascular endothelium; vascular resistance; vascular smooth muscle; vasoconstriction; vasoconstrictors

DESCRIPTION (provided by the applicant): Hypoxic pulmonary hypertension (PH) contributes to the morbidity and mortality of patients with lung and heart diseases. The pathogenesis of hypoxic PH comprises sustained pulmonary vasoconstriction and structural remodeling of pulmonary arteries. The vasoconstriction involves increased activity of the vasoconstrictors endothelin-1 (ET-1) and serotonin (5-HT), and deficient activity of the vasodilator nitric oxide (NO). This mediator imbalance is also implicated in the arterial wall thickening that includes vascular smooth muscle cell (VSMC) growth. The small GTPase RhoA is activated in VSMC by ET-1 and 5-HT, and inhibited by NO, but the role of RhoA and its downstream effector Rho-kinase in the pathogenesis of hypoxic PH is unknown. However, recent advances in the cell biology and systemic vascular pathophysiology of this signal transduction pathway, and our preliminary results, suggest that Rho/Rho-kinase signaling plays a key role in both the sustained vasoconstriction and arterial remodeling of hypoxic PH. Thus, we hypothesize that chronic hypoxia leads to activation of Rho/Rho-kinase signaling which contributes to PH by: mediating sustained pulmonary vasoconstriction, promoting VSMC growth and vascular remodeling, and regulating the expression of genes related to increased activity of ET-1 and 5-HT, and deficient production of NO. We will investigate in catheterized rats, perfused lungs, isolated pulmonary arteries, and cultured pulmonary artery cells if: 1) chronic hypoxia activates Rho/Rho-kinase signaling in pulmonary arteries, 2) Rho/Rho-kinase-induced Ca2+ sensitization of VSMC contraction mediates sustained hypoxic pulmonary vasoconstriction, and 3) chronic in vivo inhibition of Rho-kinase prevents and reverses development of hypoxic PH by suppressing vasoconstriction, vascular remodeling, and the changes in gene expression that lead to increased activity of ET-1 and 5-HT, and deficient production of NO. Our investigation of the mechanisms by which Rho/Rho-kinase signaling is activated and contributes to hypertensive pulmonary vascular tone and structure will provide new insights into the cellular mechanisms of PH. This information may lead to novel and more effective therapy for PH.

描述(由申请人提供)： 缺氧性肺动脉高压(PH)是导致心肺疾病患者发病率和死亡率的重要因素。缺氧性肺高压的发病机制包括持续的肺血管收缩和肺动脉结构重塑。血管收缩包括血管紧张剂内皮素-1(ET-1)和5-羟色胺(5-羟色胺)的活性增加，血管扩张剂一氧化氮(NO)的活性不足。这种介质失衡也与动脉壁增厚有关，包括血管平滑肌细胞(VSMC)的生长。小分子GTP酶RhoA被ET-1和5-HT激活，并被NO抑制，但RhoA及其下游效应分子Rho-Kinase在缺氧性PH发病机制中的作用尚不清楚。然而，该信号转导通路的细胞生物学和全身血管病理生理学的最新进展，以及我们的初步结果，表明Rho/Rho-Kinase信号在低氧性PH的持续血管收缩和动脉重塑中起关键作用。 因此，我们推测慢性低氧通过介导持续的肺血管收缩、促进VSMC生长和血管重塑、调节与ET-1和5-HT活性增加以及NO产生不足相关的基因表达而导致Rho/Rho-Kinase信号的激活，从而参与PH的发生。我们将在插管大鼠、灌流的肺、离体肺动脉和培养的肺动脉细胞中研究：1)慢性低氧激活肺动脉中的Rho/Rho-Kinase信号，2)Rho/Rho-Kinase诱导的VSMC对钙的敏化介导持续的缺氧性肺血管收缩，3)慢性体内抑制Rho-Kinase通过抑制血管收缩、血管重塑和导致ET-1和5-HT活性增加和NO产生不足的基因表达变化来预防和逆转缺氧性PH的发展。我们对Rho/Rho-Kinase信号被激活的机制的研究 高血压肺血管张力和结构将提供对细胞的新见解 PH的作用机制。这些信息可能会导致新的和更有效的治疗PH的方法。