Mechanisms of right ventricle adaptation to pulmonary hypertension

右心室对肺动脉高压的适应机制

基本信息

批准号：
9544366
负责人：
Tim Lahm
金额：
$ 61.46万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9544366
关键词：
APLN gene Affect Agonist Anti-Inflammatory Agents Anti-inflammatory Apoptotic Area Aromatase Inhibition Attenuated Biology Biomechanics Blood Vessels Cardiac Myocytes Cardiac development Cell physiology Cessation of life Collagen Complement Coupling Data Development Disease Dissection Distal Estradiol Estrogen Receptor alpha Estrogens Exercise Physiology Exhibits Failure Female Goals Gonadal Steroid Hormones Heart Heart failure Human Rights Hypoxia Knock-out Lead Lung Mediating Mediator of activation protein Mission Modeling Molecular Mus National Heart, Lung, and Blood Institute Pathway interactions Patients Preparation Protein-Lysine 6-Oxidase Public Health Publishing Pulmonary Heart Disease Pulmonary Hypertension Pulmonary artery structure Rattus Regulation Research Resistance Right Ventricular Function Right ventricular structure Rodent Role Signal Transduction Time Time Study Tissues Up-Regulation Ventricular Ventricular Remodeling Woman Work arterial stiffness attenuation base bone morphogenetic protein receptors collagenase crosslink electric impedance exercise capacity experimental study heart function improved in vivo inhibitor/antagonist innovation interest male new therapeutic target novel premature protective effect pulmonary arterial hypertension receptor sex tool

项目摘要

ABSTRACT This proposal builds on the scientific premise that even though right ventricular (RV) function and female sex are major determinants of survival in pulmonary arterial hypertension (PAH), no RV- or sex steroid-directed therapies exist. The goal of the proposal is to identify novel and therapeutically targetable mechanisms by which 17-estradiol (E2) exerts protective effects on RV function in PAH. We provide evidence that E2 exerts specific RV-protective effects via its receptor ER, and suggest a new mechanism by which ER activates bone morphogenetic protein receptor 2 (Bmpr2) signaling to upregulate apelin, a potent effector of RV contractility, whose regulation in the RV is not yet known. In addition to these direct effects, we show that E2 indirectly improves RV function by decreasing collagen content in the proximal pulmonary artery (PA), resulting in enhanced PA compliance and RV-PA coupling, defined as better RV adaptation to increased afterload. Based on these findings, we put forward the novel hypothesis that E2 improves RV-PA coupling in PH by ER- dependent up-regulation of cardiomyocyte apelin and by reduction of collagen content and cross-linking in the proximal PA. We propose the following aims: 1) To establish that E2 attenuates RV pro-apoptotic signaling and improves RV contractile function and contractile reserve via Bmpr2-dependent increases in apelin, 2) To identify the contribution of ER to mediating RV-protection, and 3) To demonstrate that ER improves proximal PA compliance by increasing collagenase-mediated collagen degradation and by decreasing lysyl oxidase-mediated collagen cross-linking. We generated a novel ERα knockout rat that will enable us to study the role of ERα in PA banding models (SA1&2) and in the sugen/hypoxia model (SA3), thus avoiding pitfalls of prior studies of sex hormone signaling that were limited by lack of RV failure and by E2's confounding pulmonary vascular effects. These studies will be complemented by studies of Bmpr2-deficient rats or apelin- deficient mice in SA1, and Col1a1R/R mice resistant to collagenase-mediated collagen degradation in SA3. We will complement our in vivo studies with experiments in isolated heart preparations, isolated cardiomyocytes and RV tissues from PAH patients. The proposed studies are significant, since they will 1) identify ERα as a critical modulator of RV function, 2) establish a novel and therapeutically targetable E2-ERα-Bmpr2-apelin axis in the RV, and 3) identify collagenase-mediated collagen degradation and inhibition of lysyl oxidase-mediated collagen cross-linking as functionally important mechanisms of ERα in the proximal PA. Our studies are innovative, since they, for the first time, will provide a molecular basis for E2's RV-protective effects in PAH. They provide technical innovation by use of a newly generated ERα knockout rat model and a new highly selective ERα agonist, allowing for mechanistic dissection of ERα's role in RV failure. Upon completion of the proposed studies, we will have identified ER as a novel mediator of adaptive signaling in the RV. This will allow for development of new RV-specific, non-hormonal treatments for both female and male PAH patients.

抽象的该提议建立在这样的科学前提之上：即使右心室 (RV) 功能和女性性别是肺动脉高压 (PAH) 患者生存的主要决定因素，没有 RV 或性类固醇指导该提案的目标是通过以下方式确定新颖且可治疗的靶向机制。其中 17-雌二醇 (E2) 对 PAH 中的 RV 功能发挥保护作用。通过其受体 ERα 发挥特异性 RV 保护作用，并提出了 ERα 激活的新机制骨形态发生蛋白受体 2 (Bmpr2) 信号传导上调 apelin（RV 的有效效应子）收缩性，其在 RV 中的调节尚不清楚除了这些直接影响之外，我们还表明 E2。通过减少近端肺动脉 (PA) 中的胶原蛋白含量来间接改善 RV 功能，从而增强 PA 顺应性和 RV-PA 耦合，定义为更好的 RV 适应增加的后负荷。基于这些发现，我们提出了新的假设：E2 通过 ERα- 改善 PH 中的 RV-PA 耦合心肌细胞 apelin 的依赖性上调以及通过减少胶原蛋白含量和交联我们提出以下目标：1) 确定 E2 减弱 RV 促凋亡信号传导和通过 Apelin 的 Bmpr2 依赖性增加改善 RV 收缩功能和收缩储备，2) 确定 ERα 对介导 RV 保护的贡献，以及 3) 证明 ERα 改善通过增加胶原酶介导的胶原降解和减少赖氨酰来改善近端 PA 顺应性我们培育了一种新型 ERα 敲除大鼠，这将使我们能够进行研究。 ERα 在 PA 带带模型 (SA1&2) 和 sugen/缺氧模型 (SA3) 中的作用，从而避免了以下陷阱先前对性激素信号传导的研究因缺乏 RV 衰竭和 E2 的混杂因素而受到限制对 Bmpr2 缺陷大鼠或 apelin- 的研究将补充这些研究。 SA1 缺陷小鼠和 SA3 中 Col1a1R/R 小鼠对胶原酶介导的胶原降解具有抵抗力。将通过离体心脏制剂、离体心肌细胞实验来补充我们的体内研究拟议的研究具有重要意义，因为它们将 1) 将 ERα 鉴定为一种 RV 功能的关键调节剂，2) 建立新型且可治疗靶向的 E2-ERα-Bmpr2-apelin 轴在 RV 中，3) 识别胶原酶介导的胶原降解和赖氨酰氧化酶介导的抑制胶原交联是近端 PA 中 ERα 的重要功能机制。这是创新性的，因为它们将首次为 E2 对 PAH 的 RV 保护作用提供分子基础。他们通过使用新生成的 ERα 敲除大鼠模型和新的高度选择性 ERα 激动剂，可在 RV 衰竭完成后对 ERα 的作用进行机械剖析。根据拟议的研究，我们将确定 ERα 是 RV 中适应性信号传导的新型介体。允许为女性和男性 PAH 患者开发新的 RV 特异性非激素治疗方法。