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: 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
• 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

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.

摘要 这项建议建立在这样一个科学前提之上，即尽管右心室（RV）功能和女性 是肺动脉高压（PAH）患者生存率的主要决定因素，无RV或性类固醇导向 治疗是存在的。该提案的目标是通过以下方式确定新的和治疗上可靶向的机制： 其中17 β-雌二醇（E2）对PAH时RV功能具有保护作用。我们提供的证据表明，E2发挥 特异性RV保护作用，通过其受体ER β，并提出了一种新的机制，ER β激活 骨形态发生蛋白受体2（Bmpr 2）信号传导上调爱帕琳，一种RV的有效效应物 收缩性，其在RV中的调节尚不清楚。除了这些直接的影响，我们表明，E2 通过减少近端肺动脉（PA）中的胶原含量间接改善RV功能， 增强PA顺应性和RV-PA耦合，定义为RV对增加后负荷的更好适应。 基于这些发现，我们提出了新的假说，即E2通过ER β-受体介导PH中的RV-PA偶联。 依赖性上调心肌细胞爱帕琳肽和减少胶原含量和交联， 近端PA。我们提出以下目的：1）确定E2减弱RV促凋亡信号传导， 通过Bmpr 2依赖性的爱帕琳增加改善RV收缩功能和收缩储备，2） 确定ER β对介导RV保护的贡献，以及3）证明ER β改善 通过增加胶原酶介导的胶原降解和减少赖氨酰 氧化酶介导的胶原交联。我们产生了一种新的ERα基因敲除大鼠，这将使我们能够研究 ERα在PA显带模型（SA1&2）和Sugen/缺氧模型（SA 3）中的作用，从而避免了 之前对性激素信号传导的研究受到缺乏RV失败和E2混淆的限制 肺血管效应这些研究将得到Bmpr 2缺陷大鼠或apelin-1的研究的补充。 SA 1中的缺陷型小鼠和SA 3中的对胶原酶介导的胶原降解具有抗性的Col 1a 1 R/R小鼠。我们 将补充我们在离体心脏制备实验，离体心肌细胞， 和PAH患者的RV组织。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，2）建立新的治疗靶向E2-ERα-Bmpr 2-apelin轴 3）鉴定胶原酶介导的胶原降解和赖氨酰氧化酶介导的 胶原交联是近端PA中ERα的重要功能机制。我们的研究是 这是一项创新，因为它们首次为E2在PAH中的RV保护作用提供了分子基础。 他们通过使用新产生的ERα基因敲除大鼠模型和新的高表达的 选择性ERα激动剂，允许对ERα在RV衰竭中的作用进行机械解剖。完成后 通过我们提出的研究，我们将确定ER β是RV中适应性信号传导的新介质。这将 允许为女性和男性PAH患者开发新的RV特异性非激素治疗。