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）是一种以肺血管阻力进行性增加为特征的小肺动脉疾病，可导致右心衰竭并最终死亡。多环芳烃的病因不同，但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。本应用着重于一氧化碳（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。最近的数据显示，一氧化碳是一个关键的效应分子在改善进展和/或加速血管病理在实验性肺动脉高压的消退。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（一种推定的肿瘤抑制基因）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）的重要调节因子，是eNOS产生激动剂和剪切应力刺激NO所必需的。在PAH的背景下，最近的研究发现肺动脉高压中cav-1的下调和eNOS活性的降低。一个中心假设为提出的研究计划提供了重点- CO吸入疗法通过调节caveolin-1和内皮一氧化氮合酶的表达和相互作用对PAH临床前模型产生有益影响。这一假设将通过追求以下具体目标来检验。具体目的一：建立吸入一氧化碳对临床前PAH患者血管重塑和内皮细胞功能障碍的影响。目的二：确定小窝蛋白-1介导外源性一氧化碳对实验性小鼠肺动脉高压的治疗作用。特异性目的三：确定eNOS衍生NO介导外源性CO对实验性小鼠肺动脉高压的治疗作用。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CO对多环芳烃的治疗作用中的机制作用。肺动脉高压中co诱导的细胞保护机制尚不清楚，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一氧化碳在这种使人衰弱的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.