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

描述（由申请人提供）：肺动脉高压（PAH）是一种小肺动脉疾病，其特征是肺血管阻力进行性增加，导致右心衰竭并最终死亡。PAH由不同病因引起，具有共同的病理生理学特征，包括肺血管壁重塑、血管收缩和血栓形成1。本申请集中于一氧化碳（CO）在实验性肺动脉高压小鼠模型中发挥其治疗作用的机制。最近的研究表明，CO是改善和/或加速实验性肺动脉高压血管病变进展和/或消退的关键效应分子。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（一种假定的肿瘤抑制基因）下调的能力之间存在联系。此外，cav-1是内皮型一氧化氮合酶（eNOS）的重要调节剂，并且是eNOS的激动剂和剪切应力刺激的NO产生所需的。在PAH的背景下，最近的研究揭示了肺动脉高压中cav-1的下调和eNOS活性的降低。一个中心假设为拟议的研究计划提供了焦点- CO吸入治疗通过调节小窝蛋白-1和内皮型一氧化氮合酶的表达和相互作用对PAH临床前模型发挥有益作用。将通过追求以下具体目标来检验这一假设。具体目的I：确定吸入CO对临床前PAH患者血管重塑和内皮细胞功能障碍的疗效。具体目的II：确定小窝蛋白-1在介导外源性CO对实验性小鼠肺动脉高压的治疗作用中的作用。具体目标三：探讨eNOS源性NO在外源性CO治疗实验性肺动脉高压中的作用。拟议的研究计划是基于强有力的初步数据的基础上，旨在揭示cav-1和eNOS/NO在吸入CO治疗PAH中的机制作用。由于对CO诱导的肺动脉高压细胞保护机制知之甚少，因此强调了这项研究的重要性。在完成拟议的研究后，我们将有一个更好的基础，在此基础上研究吸入CO在这种衰弱性疾病中的新的治疗用途。

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.