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

细胞外cAMP在肺动脉高压发病机制中的作用

基本信息

批准号：
9884556
负责人：
Yassine Sassi
金额：
$ 17.06万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-20 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884556
关键词：
ATP-Binding Cassette Transporters Active Biological Transport Adenosine Adenosine Monophosphate Adenylate Cyclase Adrenergic Agents Affect Animal Model Area Arteries Attenuated Biopsy Blood Platelets Blood Vessels Cardiac Cardiac Myocytes Cardiac development Cell Proliferation Cell surface Cells Cessation of life Chemicals Chronic Coupled Cyclic AMP Diagnosis Disease Distal Endothelial Cells Endothelium Extracellular Space Family Fibroblasts Fibrosis Functional disorder Goals Growth Heart Heart Hypertrophy Heart failure Homeostasis Hypertrophy Hypoxia In Vitro Inflammatory Infusion procedures Intervention Left Life Lung Mediating Messenger RNA Metabolism Modeling Molecular Mus Myocardium Outcome Pathogenesis Pathologic Pathway interactions Patients Periodicity Phenotype Physiological Play Process Proteins Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Purinergic P1 Receptors Quality of life Rattus Reporting Role Signal Transduction Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Therapeutic Vascular Diseases Vascular remodeling cell growth cell motility cell type coronary fibrosis drug development exercise capacity experimental study extracellular improved in vivo in vivo Model inhibitor/antagonist insight loss of function member migration novel therapeutic intervention novel therapeutics paracrine prevent protein expression pulmonary arterial hypertension receptor

项目摘要

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.

项目概要肺动脉高压（PAH）是一种以肺动脉进行性重塑为特征的疾病。远端肺动脉，导致血管横截面积损失和升高肺血管阻力。如果不进行干预，PAH 通常会进展，导致右心力衰竭和死亡。肺血管重塑包括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增殖，最近发现 ATP 结合盒 (ABC) 转运蛋白家族可以主动将 cAMP 转运出细胞。此外，我们最近报道分泌的心肌细胞-cAMP进入细胞外空间是一种心肌中重要的旁分泌因子，还可以保护心脏免受肾上腺素能诱导的影响肥大和纤维化。细胞外 cAMP 代谢为腺苷，腺苷激活其在多个细胞中表达的受体。因为已知腺苷是一种有效的抑制剂血管重塑（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通过使用细胞外 cAMP 通路作为逆转的治疗方法进行重塑 PAH的病理变化。该提案的具体目标是：1）定义肺动脉细胞中的细胞外cAMP通路，2)评估细胞外cAMP的作用对血管细胞增殖和迁移的影响，以及确定其机制，3）评估内源性分泌型 cAMP 对肺血管细胞的影响，4) 研究 PAH 体内模型中的细胞外 cAMP 输注。定义其存在和机制细胞外 cAMP 通路及其生理后果将在 PAH 疾病分析。靶向细胞外 cAMP 通路可能是一种有用的策略预防和治疗肺动脉高压。