The emerging role of apelin, RAAS, and ACE2 crosstalk in pulmonary hypertension

apelin、RAAS 和 ACE2 串扰在肺动脉高压中的新作用

• 批准号: 10674620
• 负责人: Andrea Lee Frump
• 金额: $ 78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674620
• 关键词: ACE2; APLN gene; Agonist; Angiotensin-Converting Enzyme Inhibitors; Blood Vessels; Cardiac; Cardiac Myocytes; Cells; Cessation of life; Clinical; Data; Development; Disease; Drug Delivery Systems; Endothelial Cells; Experimental Models; Functional disorder; Goals; Heart; Human; Impairment; Industry; Link; Lung; Mediating; Mediator; Mission; Modeling; Molecular; National Heart, Lung, and Blood Institute; Nuclear; Nuclear Receptors; Oral; Outcome; Pathway interactions; Patient Rights; Patients; Peptides; Peptidyl-Dipeptidase A; Public Health; Publishing; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Renin-Angiotensin-Aldosterone System; Research; Right Ventricular Function; Rodent Model; Role; Signal Pathway; Signal Transduction; Testing; Therapeutically Targetable; Tissues; Vasodilation; Ventricular; Work; angiogenesis; heart function; improved; in vivo; induced pluripotent stem cell; interest; mortality; novel; prevent; protective effect; pulmonary artery endothelial cell; pulmonary vascular remodeling; pulmonary vasoconstriction; receptor; receptor-mediated signaling; right ventricular failure; right ventricular remodeling; targeted treatment; treatment strategy

PROJECT SUMMARY This proposal builds on the scientific premise that right ventricular (RV) maladaptive remodeling is a major contributor to RV failure and mortality in pulmonary hypertension (PH). Despite its importance, no RV-directed therapies exist. The goal of this proposal is to is to identify 1) whether Apelin prevents RV failure and 2) whether Apelin-mediated protection is dependent on abrogation of RAAS and activation of ACE2. We provide evidence that treatment with Apelin can prevent ventricular-vascular uncoupling in vivo. We also provide evidence in human induced pluripotent stem cell cardiomyocytes (iPSC-SMs), RV-specific endothelial cells (RVECs), and pulmonary artery endothelial cells (PAECs) that treatment with Apelin increases the expression of Angiotensin- converting enzyme (ACE2) and decreases the expression of Renin-Angiotensin-Aldosterone System (RAAS) signaling mediator ACE1, potentially linking these pathways. Intriguingly, our evidence also demonstrates that 1) Apelin and ACE2 are decreased in PH models and cells 2) ACE1 is increased, and 3) Apelin receptor nuclear localization in control but not PH patient RV tissue and cells, suggesting a possible mechanism of action. However, the interaction between these pathways during RV failure and whether Apelin-mediated RV adaptation is dependent on enhancement of ACE2 signaling remains elusive. Based on these findings, we put forward the hypothesis that Apelin signaling abrogates PH-induced RV-pulmonary artery (PA) uncoupling by inhibiting RAAS and enhancing ACE2 signaling. To test our hypothesis, we propose the following aims: 1) To determine if Apelin receptor-mediated signaling promotes RV adaptative remodeling and survival through the inhibition of RAAS and activation of ACE2 2) To demonstrate that impaired nuclear localization of the Apelin receptor (APLNR) contributes to RV failure and PH development 3) To identify whether Apelin-mediated inhibition of RAAS and enhancement of ACE2 abrogates pulmonary vascular remodeling. The proposed studies are significant; they will ascertain whether Apelin is a critical mediator of RV adaptive remodeling in PH, which if true, may establish a novel and therapeutically targetable Apelin-mediated signaling axis in the RV. Targeting Apelin signaling is of particular importance: inhibition of RAAS signaling has led to mixed clinical outcomes in PH patients and drug delivery of ACE2 remains a substantial challenge. In contrast, recent industry interest has led to the development of several orally deliverable Apelin/APLNR agonists, therefore, if Apelin protection against PH is dependent on RAAS inhibition and enhancement of ACE2 in the RV and pulmonary vasculature, it would provide the rationale to use these novel Apelin/APLNR agonists to target RAAS, ACE2 and treat PH. Upon completion of the proposed studies, we will have demonstrated that by leveraging the Apelin signaling pathway, we can promote RV adaptive remodeling. Identification of pathways and targets engaged by Apelin during RV failure will allow for the development of novel, long-acting and targeted treatment strategies for the PA-RV circuit.

项目概要 该提议建立在右心室 (RV) 适应不良重塑是一个主要因素的科学前提之上。 导致右心室衰竭和肺动脉高压 (PH) 死亡的因素。尽管它很重要，但没有针对 RV 的 治疗方法是存在的。该提案的目标是确定 1) Apelin 是否可以防止 RV 故障以及 2) 是否 Apelin 介导的保护依赖于 RAAS 的废除和 ACE2 的激活。我们提供证据 Apelin 治疗可以防止体内心室血管解偶联。我们还提供了证据 人诱导多能干细胞心肌细胞 (iPSC-SM)、RV 特异性内皮细胞 (RVEC) 和 使用 Apelin 治疗的肺动脉内皮细胞 (PAEC) 会增加血管紧张素的表达 转换酶 (ACE2) 并降低肾素-血管紧张素-醛固酮系统 (RAAS) 的表达 信号传导介质 ACE1，可能连接这些通路。有趣的是，我们的证据还表明 1) Apelin 和 ACE2 在 PH 模型和细胞中减少 2) ACE1 增加，以及 3) Apelin 受体核 定位于对照而非 PH 患者 RV 组织和细胞中，表明可能的作用机制。 然而，RV 衰竭期间这些途径之间的相互作用以及 Apelin 介导的 RV 适应是否 是否依赖于 ACE2 信号传导的增强仍然难以捉摸。基于这些发现，我们提出 假设 Apelin 信号通过抑制 RAAS 消除 PH 诱导的 RV-肺动脉 (PA) 解偶联 并增强 ACE2 信号传导。为了检验我们的假设，我们提出以下目标：1）确定 Apelin 是否 受体介导的信号传导通过抑制 RAAS 促进 RV 适应性重塑和存活 和 ACE2 的激活 2) 证明 Apelin 受体 (APLNR) 的核定位受损 导致 RV 衰竭和 PH 发展 3) 确定 Apelin 介导的 RAAS 抑制和 ACE2 的增强会消除肺血管重塑。拟议的研究意义重大；他们 将确定 Apelin 是否是 PH 中 RV 适应性重塑的关键介质，如果属实，则可能会建立 RV 中新型且可治疗靶向的 Apelin 介导的信号轴。靶向 Apelin 信号传导是 特别重要的是：抑制 RAAS 信号传导导致 PH 患者和药物的临床结果混合 ACE2 的交付仍然是一个巨大的挑战。相比之下，最近的行业兴趣导致了发展 因此，如果 Apelin 对 PH 的保护作用依赖于几种口服 Apelin/APLNR 激动剂 RAAS 抑制和增强 RV 和肺血管中的 ACE2，这将提供基本原理 使用这些新型 Apelin/APLNR 激动剂来靶向 RAAS、ACE2 并治疗 PH。完成提议后 研究中，我们将证明通过利用 Apelin 信号通路，我们可以促进 RV 适应性 重塑。识别 RV 故障期间 Apelin 参与的途径和目标将允许 开发针对 PA-RV 回路的新型、长效和靶向治疗策略。

项目成果

Pathophysiology and new advances in pulmonary hypertension.

• DOI: 10.1136/bmjmed-2022-000137
• 发表时间: 2023
• 期刊: BMJ medicine
• 作者: Bousseau, Simon;Fais, Rafael Sobrano;Gu, Sue;Frump, Andrea;Lahm, Tim
• 通讯作者: Lahm, Tim