The role of extracellular cAMP in the pathogenesis of pulmonary arterial hypertension

项目摘要 肺动脉高压(PAH)是一种以血管进行性重构为特征的疾病 远端肺动脉，导致血管横截面积丧失和抬高 肺血管阻力。在没有干预的情况下，PAH通常是渐进的，导致向右 心力衰竭和死亡。肺血管重塑包括血管的增殖和迁移。 肺动脉平滑肌细胞、内皮细胞和成纤维细胞。多项研究表明 增加细胞内环磷酸腺苷(CAMP)水平会导致 血管细胞在体外和体内的增殖，最近发现血管成员 三磷酸腺苷结合盒(ABC)转运体家族可以主动地将cAMP转运出细胞。 此外，我们最近报道，心肌细胞-cAMP分泌到细胞外间隙是一种 心肌中重要的旁分泌因子，也可保护心脏免受肾上腺素诱导 肥大和纤维化。胞外cAMP被代谢成腺苷，腺苷激活其 在几个细胞中表达的受体。因为众所周知，腺苷是一种有效的抑制 血管重塑(通过其Gs蛋白偶联受体)，我们的目标是研究 肺血管细胞的胞外cAMP途径。我们的目标是减少肺血管 利用细胞外cAMP途径进行重塑以逆转 PAH的病理改变。这项提案的具体目的是：1)定义 肺动脉细胞胞外cAMP途径，2)评价胞外cAMP的作用 对血管细胞的增殖和迁移，以及其机制的确定，3)评估 内源性分泌型cAMP对肺血管细胞的影响及4)探讨内源性cAMP对肺血管内皮细胞的影响 细胞外cAMP输注在PAH体内模型中的作用。定义的存在和机制 胞外cAMP途径及其生理后果将在 对PAH病的分析。靶向胞外cAMP途径可能是一种有用的策略 防治肺动脉高压。

Project Summary Pulmonary arterial hypertension (PAH) is a disease characterized by the progressive remodeling of the distal pulmonary arteries, resulting in the loss of vascular cross-sectional area and elevated pulmonary vascular resistance. Without intervention, PAH is usually progressive, leading to right heart failure and death. Pulmonary vascular remodeling includes the proliferation and migration of pulmonary artery smooth muscle cells, endothelial cells and fibroblasts. Several studies have shown that increasing intracellular cyclic adenosine monophosphate (cAMP) levels result in a reduction of vascular cells proliferation in vitro and in vivo, and it has recently been discovered that members of the ATP-binding cassette (ABC) transporters family can actively transport cAMP out of cells. Moreover, we recently reported secreted cardiomyocyte-cAMP into the extracellular space to be an important paracrine factor in the myocardium that also protects the heart from adrenergically induced hypertrophy and fibrosis. Extracellular cAMP is metabolized to adenosine, which activates its receptors that are expressed in several cells. Because adenosine is known to be a potent inhibitor of vascular remodeling (through its Gs protein-coupled receptors), we aim to study the presence of the extracellular cAMP pathway in pulmonary vascular cells. Our goal is to attenuate pulmonary vascular remodeling by using the extracellular cAMP pathway as a therapeutic approach to reverse the pathological changes in PAH. The specific aims of this proposal are: 1) to define the presence of the extracellular cAMP pathway in pulmonary artery cells, 2) to evaluate the effects of extracellular cAMP on vascular cells proliferation and migration, as well as determining its mechanism, 3) to assess the effects of endogenous secreted-cAMP in pulmonary vascular cells and 4) to investigate the impact of extracellular cAMP infusion in in vivo models of PAH. Defining the presence and the mechanisms of the extracellular cAMP pathway and its physiological consequences will be of great relevance in the analysis of the PAH disease. Targeting the extracellular cAMP pathway might be a useful strategy to prevent and treat pulmonary hypertension.