Pulmonary Vascular-Right Ventricular Axis Research Program

肺血管-右心室轴研究计划

• 批准号: 8355145
• 负责人: Serpil C. Erzurum
• 金额: $ 67.32万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8355145
• 关键词: 2-Fluoro-2-deoxyglucose; Adenylate Cyclase; Adrenergic Receptor; Agonist; Apoptosis; Binding; Biochemical; Blood Vessels; Cardiac; Cardiac Myocytes; Cause of Death; Cells; Clinical Trials; Clinical assessments; Cyclic AMP; Data; Deoxyglucose; Development; Disease; Down-Regulation; Endothelial Cells; Endothelium; Enzymes; Event; Failure; Fasting; Figs - dietary; Functional disorder; Goals; Growth; Health; Heart; Heart failure; Human; Investigation; Knowledge; Lead; Left; Link; Longitudinal Studies; Lung; Mediating; Metabolic; Metabolism; Modeling; Muscle Cells; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Placebo Control; Play; Positron-Emission Tomography; Production; Protein Dephosphorylation; Protein Kinase; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Pulmonary Hypertension; Pulmonary artery structure; Receptor Signaling; Recovery; Recycling; Regulation; Research; Resistance; Role; Serine; Signal Transduction; Signal Transduction Pathway; Testing; Threonine; Time; Transducers; Vascular remodeling; Ventricular; carvedilol; desensitization; functional improvement; functional restoration; functional status; glucose analog; hemodynamics; human NOS3 protein; hypoxia inducible factor 1; in vivo; novel; pressure; programs; pulmonary arterial hypertension; receptor; receptor downregulation; receptor function; response; uptake

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a fatal disease characterized by impaired regulation of pulmonary hemodynamics and vascular growth; right ventricular failure is the leading cause of death. Our studies have identified loss of pulmonary vascular endothelial nitric oxide synthase (eNOS) activity in PAH, and that the NO deficiency leads to hypoxia-inducible factor-1 (HIF-1) activation, which results in glycolytic, proliferative, apoptosis-resistant endothelial cells that promote vascular remodeling. The mechanism(s) of eNOS activity loss is unknown. eNOS is also present in the cardiomyocyte, where NO synthesis by eNOS is cardioprotective; but eNOS has not been studied in the human PAH heart. Activation of eNOS requires enzyme dephosphorylation at Threonine 495 (T495) and phosphorylation at Serine 1177 (S1177), the latter mediated by cyclic adenosine monophosphate (cAMP)/protein kinase pathways downstream of ?-Adrenergic Receptors (?AR) [Fig 1]. Because ?AR downregulation and desensitization are found in all heart failure, we investigated ?AR in the eNOS activity loss and its consequences on the pulmonary vascular-right ventricular (RV) axis. Explanted human PAH hearts have desensitization and low numbers of ?AR, and for the first time, we show that pulmonary arterial endothelial cells (PAEC) from human PAH lungs have similarly low numbers and de- sensitization of ?AR. Preliminary data reveal that ?AR desensitization is due to deficient dephosphorylation of the receptor by phosphatases, which are inhibited by over-activation of phosphatidyl inositol 3-kinase (PI3Kg). ?AR numbers are low due to defective intracellular recycling of phosphorylated receptors. Consistent with PI3K inhibition of phosphatases, PAH PAEC and cardiomyocytes have high levels of the inactive pT495 eNOS, identifying the cause of decreased NO production upon any type of agonist stimulation, i.e. eNOS is in an inactive state. As in the endothelial cell, NO deficiency in PAH hearts is associated with greater HIF-activation and increased glycolytic metabolism as identified by glycolytic enzyme expression and uptake of the glucose analogue [18F]2-fluoro-2-deoxy-D-glucose by positron emission tomography (fasting FDG-PET) in PAH patients. Exciting preliminary studies indicate that b-blockers reverse ?AR dysfunction, restore phosphatase- mediated eNOS activation, and thus increase cAMP and NO production, respectively. Thus, we hypothesize that cardiomyocytes and endothelial cells in PAH suffer from interconnected abnormalities of ?AR function and eNOS activation that lead to a HIF-mediated maladaptive vascular and cardiomyocyte phenotype, all of which is reversible by ?-blocker. We test this hypothesis PAEC derived from patients' lungs, explanted human hearts, and in a mechanistic longitudinal study of ?AR blockade in PAH patients. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a fatal disease associated with increased pulmonary artery pressure and abnormalities in blood vessel growth. Heart failure is the primary cause of death, but current therapies focus entirely on treating the pulmonary hypertension. The determinants of heart failure are unknown. Some patients have adaptive responses of the heart and retain good function for years, while others have progressive heart failure. The goal of this study is to discover the fundamental mechanisms underlying the development and progression of heart failure so that we can use the knowledge to develop successful strategies for comprehensive treatment of the pulmonary hypertension and heart failure.

描述（由申请人提供）：肺动脉高压（PAH）是一种致命疾病，其特征是肺血液动力学和血管生长的调节受损；右心衰竭是死亡的主要原因。我们的研究已经确定了PAH中肺血管内皮一氧化物合酶（ENOS）活性的丧失，没有缺乏会导致缺氧诱导因子1（HIF-1）激活，从而导致糖酵解，增殖性，凋亡性，抑制 - 抗性内皮细胞促进血管重塑。 eNOS活性损失的机制尚不清楚。 eNOS也存在于心肌细胞中，那里没有eNOS的合成是心脏保护。但是eNOS尚未在人类的心脏中进行研究。 eNOS的激活需要在苏氨酸495（T495）时进行酶去磷酸化，而丝氨酸1177（S1177）的磷酸化，后者是由环环腺苷（CAMP）/蛋白质激酶途径介导的。因为在所有心力衰竭中都发现了AR下调和脱敏，所以我们研究了eNOS活性损失及其对肺血管右室（RV）轴的后果。受外植的人类PAH心脏具有脱敏和较少的？初步数据表明，AR脱敏是由于磷酸酶对受体的脱磷酸化不足，而磷脂酰肌醇3-激酶（PI3KG）抑制了受体。由于磷酸化受体的细胞内回收缺陷，AR数量较低。与PI3K抑制磷酸酶一致，PAH PAEC和心肌细胞具有高水平的无活性PT495 eNOS，从而确定了任何类型的激动剂刺激，即eNOS在不活动状态下降低了无产生的原因。与内皮细胞一样，PAH心脏的缺乏与通过糖酵解酶表达和葡萄糖类似物的吸收[18F] 2-氟-2-脱氧-D-葡萄糖的吸收来确定，与葡萄糖表达和吸收良好相关。令人兴奋的初步研究表明，B阻滞剂会逆转功能障碍，恢复磷酸酶介导的ENOS激活，从而分别增加cAMP和无生产。因此，我们假设PAH中的心肌细胞和内皮细胞患有互连的异常功能和eNOS激活，导致HIF介导的疾病疾病疾病的疾病疾病和心肌细胞表型，所有这些都是可逆的。我们在PAH患者中对患者的肺部，外植的人心脏以及对AR阻滞的机械纵向研究中得出的这一假设PAEC。 公共卫生相关性：肺动脉高压（PAH）是一种致命疾病，与肺动脉压力增加和血管生长异常有关。心力衰竭是死亡的主要原因，但当前的疗法完全集中于治疗肺动脉高压。心力衰竭的决定因素未知。一些患者对心脏有适应性反应，并保持良好的功能多年，而另一些患者则具有渐进的心力衰竭。这项研究的目的是发现心力衰竭发展和发展的基本机制，以便我们可以利用知识来制定成功的策略来全面治疗肺动脉高压和心力衰竭。