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

• 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
• 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

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.

项目摘要 肺动脉高压（PAH）是一种以肺动脉进行性重构为特征的疾病， 远端肺动脉，导致血管横截面积的损失和升高 肺血管阻力如果不进行干预，PAH通常是进行性的， 心力衰竭和死亡。肺血管重构包括肺动脉内皮细胞的增殖和迁移， 肺动脉平滑肌细胞、内皮细胞和成纤维细胞。几项研究表明 细胞内环磷酸腺苷（cAMP）水平的增加导致细胞内 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地将cAMP转运出细胞。 此外，我们最近报道，分泌到细胞外空间的心肌细胞cAMP是一个重要的细胞因子。 心肌中重要的旁分泌因子，也保护心脏免受肾上腺素能诱导的 肥大和纤维化。细胞外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），我们的目的是研究存在的 细胞外cAMP途径。我们的目标是减弱肺血管 通过使用细胞外cAMP途径作为治疗方法来逆转 PAH的病理变化。该提案的具体目标是：1）界定 肺动脉细胞的细胞外cAMP途径，2）评估细胞外cAMP的作用 对血管细胞增殖和迁移的影响，并探讨其作用机制; 内源性分泌型cAMP在肺血管细胞中的作用和4）研究 PAH体内模型中的细胞外cAMP输注。界定存在和机制， 细胞外cAMP途径及其生理后果将在 肺动脉高压疾病分析。靶向细胞外cAMP途径可能是一种有用的策略， 防治肺动脉高压。