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.

项目摘要 该提议建立在科学前提的基础上，即右心（RV）适应不良的改造是主要的 肺动脉高压（pH）中RV衰竭和死亡率的贡献者。尽管它很重要，但没有RV导向 存在疗法。该建议的目的是确定1）APELIN是否防止RV失败，2）是否是否 Apelin介导的保护取决于RAAS的废除和ACE2的激活。我们提供证据 用丙法蛋白治疗可以防止体内的心室血管解偶联。我们还提供证据 人诱导的多能干细胞心肌细胞（IPSC-SMS），RV特异性内皮细胞（RVEC）和 肺动脉内皮细胞（PAECS）用丙蛋白酶治疗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 信号介体ACE1，可能会连接这些途径。有趣的是，我们的证据也表明 1）pH模型和细胞中的Apelin和ace2降低2）ACE1增加，3）Apelin受体核核 在对照中定位，而不是pH患者RV组织和细胞，这表明可能的作用机理。 但是，在RV失败期间这些途径之间的相互作用以及Apelin介导的RV适应是否 取决于ACE2信号的增强仍然难以捉摸。根据这些发现，我们提出了 Apelin信号传导通过抑制RAAS消除pH诱导的RV肺动脉（PA）解偶联的假设 并增强ACE2信号。为了检验我们的假设，我们提出以下目的：1）确定apelin是否是 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 ACE2 2）激活APELIN受体（APLNR）的核定位置受损 有助于RV衰竭和pH开发3）确定Apelin介导的RAAS抑制和 ACE2的增强废除了肺血管重塑。拟议的研究很重要。他们 将确定APELIN是否是RV自适应重塑pH中的关键介体，如果是真的，则可以建立 RV中的一种新颖且具有治疗靶向的Apelin介导的信号轴。靶向Apelin信号是 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的交付仍然是一个重大挑战。相比之下，最近的行业兴趣导致了发展 因此 RAAS抑制和增强RV和肺脉管系统中ACE2的增强，它将提供理由 使用这些新型的apelin/aplnr激动剂来靶向raas，ace2和治疗pH。提议完成后 研究，我们将证明，通过利用Apelin信号通路，我们可以促进RV自适应 重塑。识别Apelin在RV失败期间涉及的途径和目标将允许 开发PA-RV电路的新型，长效和针对性的治疗策略。

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