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：
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
项目类别：
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

项目摘要

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.

抽象的该提议建立在这样的科学前提之上：尽管女性是疾病的主要调节因素肺动脉高压（PAH），雌激素对右心室（RV）和肺动脉的影响 PAH 中的 (PA) 是多效性的且尚未完全了解，我们认为选择性激活雌激素受体。 (ER)α 信号传导是一种利用 RV-PA 单元中保护性雌激素效应的更精确方法，该提案的目标是确定新颖的治疗方法。 ERα 对 RV-PA 单元的所有三个区室发挥保护作用的靶向机制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 (BMPR2) 信号传导上调 RV 和远端 PA 中的 apelin，并通过我们努力减少近端 PA 中的胶原蛋白积累，以改善 RV-PA 耦合。 PAH 通过 1) 上调心肌细胞 apelin，2) 减少近端 PA 胶原蛋白积累和交联， 3) 预防 PA 内皮细胞 (PAEC) 凋亡我们提出以下目标： 1) 测试 ERα 是否存在。通过 BMPR2 依赖性增加，减弱 RV 促凋亡信号并改善 RV 收缩功能 apelin，2) 证明 ERα 增加胶原酶介导的胶原降解并减少赖氨酰近端 PA 中氧化酶家族介导的胶原交联，以及 3) 确定 ERα 是否降低通过 BMPR2 和 apelin 依赖性机制，远端 PA 中的 EC 细胞凋亡我们产生了新的 ERα。敲除大鼠以研究 ERα 在 RV 衰竭的稳健模型中的作用，从而避免先前性别研究的陷阱激素信号传导因缺乏 RV 衰竭和缺乏对整个 RV-PA 单元的询问而受到限制。这些研究将通过对 BMPR2 缺陷大鼠和 apelin 缺陷小鼠的研究来补充。 SA1&3 和 Col1a1R/R 小鼠对 SA2 中胶原酶介导的胶原降解具有抵抗力。我们的体内研究是从患有 PH 和 RV 的啮齿动物中分离出心肌细胞和 PAEC 进行实验拟议的研究具有重要意义，因为它们将 1) 将 ERα 识别为一种 RV 功能的关键调节剂，并在 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 功能上重要的机制，并且 3）建立了 up- BMPR2 和 apelin 的调节作为 ERα 在远端 PA 中的新作用机制。因为他们将 ERα 确定为增强 RV-PA 耦合的新型介体，从而提供了技术创新。完成后，使用新生成的 ERα 敲除大鼠模型和新的高选择性 ERα 激动剂。在拟议的研究中，我们将确定 ERα 激活在所有三个区室中的“净效应” RV-PA 单元并确定 ERα 作为直接和间接 RV 保护作用的有效介质。允许开发针对 RV 和 PA 的新型非激素疗法。