Mechanisms of Right Ventricle Adaptation to Pulmonary Hypertension

摘要 这一建议建立在一个科学前提上，即尽管女性性行为是 肺动脉高压(PAH)--雌激素对右心室(RV)和肺动脉的影响 (PA)在多环芳烃中是多效性的，并且不完全被理解。我们假设选择性地激活雌激素受体 (ER)α信号是在RV-PA单位中利用保护性雌激素效应的更精确的方法 在避免损害的同时实现利益最大化。这项提议的目标是在治疗上发现新奇的 ERα对RV-PA单位的所有三个隔室发挥保护作用的靶向机制 啊哈。我们提供的证据表明，ERα通过活化骨发挥直接和间接的RV保护作用 形态发生蛋白受体2(BMPR2)信号在RV和PA远端上调apelin，并通过 减少PA近端的胶原堆积。我们假设ERα改善了RV-PA偶联。 PAH通过1)上调心肌细胞apelin，2)减少PA近端胶原堆积和交联， (3)防止PA内皮细胞(PAEC)凋亡。我们提出了以下目标：1)测试ERα 通过BMPR2依赖的增加抑制RV促凋亡信号，改善RV收缩功能 Apelin，2)证明ERα促进胶原酶介导的胶原降解并降低赖氨酸 3)确定内质网α是否降低。 内皮细胞通过BMPR2和apelin依赖的机制在PA远端发生细胞凋亡。我们产生了新颖的ERα 基因敲除大鼠研究ERα在RV失败的健壮模型中的作用，从而避免先前性别研究的陷阱 激素信号受到RV故障和整个RV-PA单位缺乏讯问的限制。 这些研究将得到对BMPR2缺陷大鼠和apelin缺陷小鼠的研究的补充 SA1&3和Col1a1R/R小鼠抵抗胶原酶介导的胶原蛋白在SA2中的降解。我们将互为补充 我们对PH和RV啮齿动物的心肌细胞和PAECs的体内实验研究 来自PAH患者的组织和PAECs。拟议的研究具有重要意义，因为它们将1)确定ERα是一种 RV功能的关键调节剂和建立新的具有治疗靶向的ERα-BMPR2-apelin轴 RV，2)建立胶原酶介导的胶原降解和抑制赖氨酸氧化酶家族介导的胶原降解 胶原蛋白的交联是内质网α在PA近端的重要作用机制。 调控bmpr2和apelin是ERα在远端PAS中作用的新机制。我们的研究是创新的， 因为他们将ERα确定为增强RV-PA偶联的一种新的介体。提供技术创新 通过使用新产生的ERα基因敲除大鼠模型和一种新的高选择性ERα激动剂。完工后 在拟议的研究中，我们将确定ERα激活在所有三个区域的净影响 RV-PA单位和建立ERα作为直接和间接RV保护作用的有效中介。这将是 允许开发针对RV和PA的新型非激素疗法。

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.