Mechanisms of Right Ventricle Adaptation to Pulmonary Hypertension

右心室对肺动脉高压的适应机制

• 批准号: 10001599
• 负责人: Tim Lahm
• 金额: $ 70.65万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001599
• 关键词: APLN gene; Agonist; Apoptosis; Apoptotic; Attenuated; Biology; Biomechanics; Blood Vessels; Cardiac Myocytes; Cardiac development; Cell physiology; Cessation of life; Collagen; Complement; Coupling; Data; Development; Disease; Distal; Endothelial Cells; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exercise Physiology; Failure; Family; Female; Goals; Gonadal Steroid Hormones; Heart failure; Investigation; Knock-out; Knowledge; Longevity; Lung; Mediating; Mediator of activation protein; Mission; Modeling; Mus; Muscle; National Heart, Lung, and Blood Institute; Patients; Protein-Lysine 6-Oxidase; Public Health; Publishing; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Rattus; Research; Resistance; Right ventricular structure; Rodent; Role; Signal Pathway; Signal Transduction; Survival Rate; Testing; Time; Tissues; Up-Regulation; Vascular Diseases; Work; base; bone morphogenetic protein receptors; clinically relevant; collagenase; crosslink; electric impedance; estrogenic; exercise capacity; experimental study; heart function; hormonal signals; improved; in vivo; innovation; male; new therapeutic target; novel; premature; prevent; protective effect; pulmonary arterial hypertension; pulmonary artery endothelial cell; sex; targeted treatment

ABSTRACT This proposal builds on the scientific premise that even though female sex is a major disease modifier in pulmonary arterial hypertension (PAH), the effects of estrogens on the right ventricle (RV) and pulmonary artery (PA) in PAH are pleiotropic and incompletely understood. We posit that selectively activating estrogen receptor (ER)α signaling is a more precise approach of harnessing protective estrogenic effects in the RV-PA unit that maximizes benefit while avoiding detriment. The goal of this proposal is to identify novel and therapeutically targetable mechanisms by which ERα exerts protective effects on all three compartments of the RV-PA unit in PAH. We provide evidence that ERα exerts direct and indirect RV-protective effects by activating bone morphogenetic protein receptor 2 (BMPR2) signaling to upregulate apelin in the RV and distal PA, and by decreasing collagen accumulation in the proximal PA. We hypothesize that ERα improves RV-PA coupling in PAH by 1) up-regulating cardiomyocyte apelin, 2) reducing proximal PA collagen accumulation and cross-linking, and 3) preventing PA endothelial cell (PAEC) apoptosis. We propose the following aims: 1) To test whether ERα attenuates RV pro-apoptotic signaling and improves RV contractile function via BMPR2-dependent increases in apelin, 2) To demonstrate that ERα increases collagenase-mediated collagen degradation and decreases lysyl oxidase family-mediated collagen cross-linking in the proximal PA, and 3) To determine whether ERα decreases EC apoptosis in the distal PA through a BMPR2- and apelin-dependent mechanism. We generated novel ERα knockout rats to study the role of ERα in robust models of RV failure, thus avoiding pitfalls of prior studies of sex hormone signaling that were limited by lack of RV failure and by lack of interrogation of the entire RV-PA unit. These studies will be complemented by investigations in BMPR2-deficient rats and apelin-deficient mice in SA1&3, and Col1a1R/R mice resistant to collagenase-mediated collagen degradation in SA2. We will complement our in vivo studies with experiments in cardiomyocytes and PAECs isolated from rodents with PH as well as RV tissues and PAECs from PAH patients. The proposed studies are significant, since they will 1) identify ERα as a critical modulator of RV function and establish a novel and therapeutically targetable ERα-BMPR2-apelin axis in the RV, 2) establish collagenase-mediated collagen degradation and inhibition of lysyl oxidase family-mediated collagen cross-linking as functionally important mechanisms of ERα in the proximal PA and 3) establish up- regulation of BMPR2 and apelin as a novel mechanism of action of ERα in distal PAs. Our studies are innovative, since they will identify ERα as a novel mediator of enhanced RV-PA coupling. Technical innovation is provided by use of a newly generated ERα knockout rat model and a new highly selective ERα agonist. Upon completion of the proposed studies, we will have identified the “net effects” of ERα activation in all three compartments of the RV-PA unit and established ERα as a potent mediator of direct and indirect RV-protective effects. This will allow for developing novel, non-hormonal therapies targeting both the RV and PA.

摘要 这一提议建立在科学前提之上，即尽管女性性行为是一种主要的疾病修饰因素， 肺动脉高压（PAH），雌激素对右心室（RV）和肺动脉的影响 (PA)在PAH中的作用是多效性的，尚未完全了解。我们认为选择性激活雌激素受体 (ER)α信号传导是一种更精确的方法，可以利用RV-PA单位中的保护性雌激素效应， 最大化利益，同时避免损害。该提案的目标是确定新的和治疗 ERα对RV-PA单位的所有三个隔室发挥保护作用的靶向机制， 呸。我们提供的证据表明ERα通过激活骨发挥直接和间接的RV保护作用 形态发生蛋白受体2（BMPR 2）信号传导以上调RV和远端PA中的爱帕琳，并且通过 减少近端PA中的胶原积聚。我们假设ERα改善RV-PA偶联， PAH通过1）上调心肌细胞apelin，2）减少近端PA胶原积聚和交联， 3）防止PA内皮细胞（PAEC）凋亡。我们提出以下目的：1）检测ERα是否 通过BMPR 2依赖性增加，减弱RV促凋亡信号传导并改善RV收缩功能， 2）为了证明ERα增加胶原酶介导的胶原降解并减少赖氨酰化， 氧化酶家族介导的近端PA中的胶原交联，以及3）确定ERα是否降低 通过BMPR 2和apelin依赖性机制在远端PA中的EC凋亡我们产生了新的ERα 敲除大鼠研究ERα在RV衰竭的稳健模型中的作用，从而避免了先前性别研究的陷阱。 由于缺乏RV衰竭和缺乏对整个RV-PA单元的询问而限制的激素信号传导。 这些研究将通过在BMPR 2缺陷大鼠和apelin缺陷小鼠中的研究来补充， SA1&3和Col 1a 1 R/R小鼠对SA 2中胶原酶介导的胶原降解具有抗性。我们将补充 我们在从PH和RV啮齿动物中分离的心肌细胞和PAEC中进行的体内研究 PAH患者的组织和PAEC。拟议的研究是有意义的，因为它们将1）确定ERα是一种 RV功能的关键调节剂，并建立一种新的治疗靶向ERα-BMPR 2-apelin轴， 所述RV，2）建立胶原酶介导的胶原降解和赖氨酰氧化酶家族介导的抑制 胶原交联是近端PA中ERα的重要功能机制，3）建立 调节BMPR 2和apelin作为ERα在远端PA中的新作用机制。我们的研究是创新的， 因为他们将确定ERα作为增强RV-PA偶联的新介质。提供技术创新 利用新建立的ERα基因敲除大鼠模型和一种新的高选择性ERα激动剂。完成后 在这些拟议的研究中，我们将确定ERα激活在所有三个区室中的“净效应”， RV-PA单位，并建立ERα作为直接和间接RV保护作用的有效介质。这将 允许开发针对RV和PA的新型非激素疗法。