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

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

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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.

项目摘要肺动脉高压（PAH）是一种疾病，其特征是进行性重塑远端肺动脉，导致血管横截面区域丧失，并升高肺血管抗性。没有干预，PAH通常是渐进的，导致正确心力衰竭和死亡。肺血管重塑包括肺动脉平滑肌细胞，内皮细胞和成纤维细胞。几项研究表明增加细胞内循环腺苷一磷酸（CAMP）水平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营地从细胞中运出。此外，我们最近向细胞外空间报告了分泌的心肌细胞训练营心肌中重要的旁分泌因子也可以保护心脏免受肾上腺素的诱导肥大和纤维化。细胞外营地被代谢为腺苷，这激活了其在几个细胞中表达的受体。因为已知腺苷是有效的抑制剂血管重塑（通过其GS蛋白偶联受体），我们旨在研究存在肺血管细胞中的细胞外cAMP通路。我们的目标是减轻肺血管通过使用细胞外营地路径作为一种治疗方法来逆转 PAH的病理变化。该提案的具体目的是：1）定义存在肺动脉细胞中的细胞外cAMP途径，2）评估细胞外cAMP的影响关于血管细胞的增殖和迁移以及确定其机制，3）评估内源性训练营对肺血管细胞的影响，4）研究 PAH体内模型的细胞外cAMP输液。定义存在和机制细胞外营地及其生理后果将在 PAH疾病的分析。针对细胞外营地可能是一个有用的策略预防和治疗肺动脉高压。