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: 6728395
• 负责人: IVAN F MCMURTY
• 金额: $ 22.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6728395
• 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）： 低血压性肺动脉高压（hypoxia pulmonary hypertension，PH）是肺、心疾病患者的重要发病因素。缺氧性PH的发病机制包括持续性肺血管收缩和肺动脉结构重建。血管收缩涉及血管收缩剂内皮素-1（ET-1）和5-羟色胺（5-HT）的活性增加，以及血管扩张剂一氧化氮（NO）的活性不足。这种介质不平衡也涉及动脉壁增厚，包括血管平滑肌细胞（VSMC）的生长。内皮素-1和5-羟色胺可激活VSMC中的小G T激酶RhoA，而NO可抑制RhoA的活性，但RhoA及其下游效应物Rho激酶在缺氧性PH发病机制中的作用尚不清楚。然而，最近的进展，在细胞生物学和全身血管病理生理学的信号转导途径，我们的初步结果，表明，Rho/Rho激酶信号在持续的血管收缩和缺氧PH的动脉重塑中起着关键作用。 因此，我们假设慢性缺氧导致Rho/Rho激酶信号传导的激活，其通过以下方式促成PH：介导持续的肺血管收缩，促进VSMC生长和血管重塑，并调节与ET-1和5-HT活性增加和NO产生不足相关的基因表达。我们将在插管大鼠，灌注肺，离体肺动脉，和培养的肺动脉细胞，如果：1）慢性缺氧激活肺动脉中的Rho/Rho-激酶信号传导，2）Rho/Rho-激酶诱导的VSMC收缩的Ca 2+敏化介导持续的缺氧性肺血管收缩，和3）Rho-激酶的慢性体内抑制通过抑制血管收缩防止和逆转缺氧性PH的发展，血管重塑，以及导致ET-1和5-HT活性增加的基因表达变化，以及NO产生不足。我们对Rho/Rho激酶信号转导被激活并有助于 高血压肺血管张力和结构将提供新的见解， 这些信息可能会导致新的和更有效的治疗PH。