Role of Caveolin-1 and eNOS in Mediating the Therapeutic Effects of CO in PAH.

描述(申请人提供)：肺动脉高压(PAH)是一种以肺血管阻力进行性增加为特征的小肺动脉疾病，导致右心衰竭并最终死亡。PAH由不同的病因引起，具有共同的病理生理特征，包括肺血管壁重塑、血管收缩和血栓形成1。本文重点研究一氧化碳(CO)在实验性肺动脉高压小鼠模型中的治疗作用机制。最近的数据显示，CO在改善和/或加速实验性肺动脉高压血管病变的进展和/或消退方面是一个关键的效应分子。初步研究表明，CO的抗增殖作用与其阻止生长因子诱导的Cav-1下调的能力有关，Cav-1是一种假定的肿瘤抑制基因。此外，Cav-1是内皮型一氧化氮合酶(ENOS)的重要调节因子，是激动剂和切应力刺激eNOS产生NO所必需的。在PAH的背景下，最近的研究表明，在肺动脉高压中Cav-1表达下调，eNOS活性降低。一个中心假设为拟议的研究计划提供了重点-CO吸入疗法通过调节小窝蛋白-1和内皮型一氧化氮合酶的表达和相互作用，对临床前PAH模型发挥有益作用。这一假设将通过追求以下具体目标来检验。具体目的I：确定吸入CO对临床前PAH患者血管重构和内皮细胞功能障碍的疗效。特定目的II：确定小窝蛋白-1在介导外源性一氧化碳对实验性小鼠肺动脉高压治疗作用中的作用。目的III：探讨内皮型一氧化氮合酶衍生的一氧化氮在外源性一氧化碳治疗实验性小鼠肺动脉高压中的作用。拟议的研究计划基于强大的初步数据基础，旨在揭示Cav-1和eNOS/NO在吸入性CO对PAH的治疗效果中的机制作用。一氧化碳诱导的细胞保护在肺动脉高压中的机制知之甚少，这突显了这项研究的重要性。在完成拟议的研究后，我们将有更好的基础来研究吸入性一氧化碳在这种衰弱疾病中的新治疗用途。

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries marked by a progressive increase in pulmonary vascular resistance, leading to right heart failure and ultimately death. PAH arises from different etiologies that share common pathophysiological features including remodeling of the pulmonary vessel wall, vasoconstriction, and thrombosis 1. This application focuses on the mechanism by which carbon monoxide (CO) exerts its therapeutic actions in a murine model of experimental pulmonary hypertension. Recent data reveals that CO is a critical effector molecule in ameliorating the progression and/or hastening the regression of vascular pathology in experimental pulmonary hypertension. Preliminary studies demonstrate linkage between the anti-proliferative actions of CO and its ability to prevent growth factor-induced downregulation of cav-1, a putative tumor suppressor gene. In addition cav-1 is an important regulator of endothelial nitric oxide synthase (eNOS) and is required for agonist and shear stress-stimulated NO production from eNOS. In the context of PAH, recent studies reveal downregulation of cav-1 and decreased eNOS activity in pulmonary hypertension. A central hypothesis provides focus to the proposed research plan - CO inhalation therapy exerts its beneficial effects on preclinical models of PAH by modulating the expression and interaction of caveolin-1 and endothelial nitric oxide synthase. This hypothesis will be tested by pursuing the following specific aims. Specific Aim I: Establish the efficacy of inhaled CO on vascular remodeling and endothelial cell dysfunction in preclinical PAH. Specific Aim II: Determine the role caveolin-1 in mediating the therapeutic effects of exogenous CO in experimental murine pulmonary hypertension. Specific Aim III: Determine the role of eNOS derived NO in mediating the therapeutic effects of exogenous CO in experimental murine pulmonary hypertension. The proposed research plan is based on a foundation of strong preliminary data and is designed to reveal a mechanistic role for cav-1 and eNOS/NO in the therapeutic effects of inhaled CO in PAH. The importance of the proposed research is underscored by the poorly understood mechanisms of CO-induced cytoprotection in pulmonary arterial hypertension. Upon completion of the proposed research we will have a better foundation upon which to investigate the novel therapeutic use of inhaled CO in this debilitating disease.