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
基本信息
- 批准号:10674620
- 负责人:
- 金额:$ 78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:ACE2APLN geneAgonistAngiotensin-Converting Enzyme InhibitorsBlood VesselsCardiacCardiac MyocytesCellsCessation of lifeClinicalDataDevelopmentDiseaseDrug Delivery SystemsEndothelial CellsExperimental ModelsFunctional disorderGoalsHeartHumanImpairmentIndustryLinkLungMediatingMediatorMissionModelingMolecularNational Heart, Lung, and Blood InstituteNuclearNuclear ReceptorsOralOutcomePathway interactionsPatient RightsPatientsPeptidesPeptidyl-Dipeptidase APublic HealthPublishingPulmonary Heart DiseasePulmonary HypertensionPulmonary Vascular ResistancePulmonary artery structureRenin-Angiotensin-Aldosterone SystemResearchRight Ventricular FunctionRodent ModelRoleSignal PathwaySignal TransductionTestingTherapeutically TargetableTissuesVasodilationVentricularWorkangiogenesisheart functionimprovedin vivoinduced pluripotent stem cellinterestmortalitynovelpreventprotective effectpulmonary artery endothelial cellpulmonary vascular remodelingpulmonary vasoconstrictionreceptorreceptor-mediated signalingright ventricular failureright ventricular remodelingtargeted treatmenttreatment strategy
项目摘要
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.
项目总结
这一建议建立在右室(RV)适应性不良重塑是一个主要的
导致右肺功能衰竭和肺动脉高压(PH)死亡的因素。尽管它很重要,但没有房车导演的
治疗方法是存在的。这项建议的目标是确定1)阿佩林是否可以预防房车衰竭和2)阿佩林是否
Apelin介导的保护依赖于RAAS的去除和ACE2的激活。我们提供证据
用Apelin治疗可以防止体内的心室-血管解偶联。我们还提供证据在
人诱导多能干细胞心肌细胞(IPSC-SM)、RV特异性内皮细胞(RVECs)和
用Apelin处理的肺动脉内皮细胞(PAECs)增加血管紧张素-1的表达
转换酶(ACE2)和降低肾素-血管紧张素-醛固酮系统(RAAS)的表达
信号调节因子ACE1,可能连接这些通路。有趣的是,我们的证据还表明
1)PH模型及细胞Apelin和ACE2含量降低;2)ACE1含量升高;3)Apelin受体核内
定位于对照,而不是PH患者的RV组织和细胞,提示可能的作用机制。
然而,RV衰竭时这些通路之间的相互作用以及Apelin是否介导RV适应
依赖于ACE2信号的增强仍然难以捉摸。基于这些发现,我们提出了
Apelin信号通过抑制RAAS抑制PH诱导的RV-PA解偶联的假说
增强ACE2信号转导。为了验证我们的假设,我们提出了以下目标:1)确定Apelin
受体介导的信号通过抑制RAAS促进RV适应性重构和存活
和激活ACE2)来证明Apelin受体(APLNR)的核定位受损
有助于RV衰竭和PH的发展3)以确定Apelin介导的RAAS和
血管紧张素转换酶2增强可消除肺血管重塑。拟议的研究具有重要意义;它们
将确定Apelin是否是PH患者RV适应性重构的关键介质,如果是真的,可能会建立
RV中一种新的、具有治疗靶向性的Apelin介导的信号轴。靶向Apelin信号转导是
特别重要:抑制RAAS信号导致PH患者和药物的临床结果好坏参半
交付ACE2仍然是一个巨大的挑战。相比之下,最近的行业兴趣导致了这一发展
因此,如果Apelin对PH的保护依赖于
RAAS抑制和增强RV和肺血管中的ACE2,这将为RV和肺血管系统ACE2的表达提供理论基础
目的:利用这些新型Apelin/APLNR激动剂靶向RAAS、ACE2和治疗PH。在完成建议的
研究表明,通过利用Apelin信号通路,我们可以促进RV适应
改建。在RV故障期间识别Apelin参与的路径和目标将允许
为PA-RV回路开发新的、长效的和有针对性的治疗策略。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Pathophysiology and new advances in pulmonary hypertension.
- DOI:10.1136/bmjmed-2022-000137
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Bousseau, Simon;Fais, Rafael Sobrano;Gu, Sue;Frump, Andrea;Lahm, Tim
- 通讯作者:Lahm, Tim
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Andrea Lee Frump其他文献
Andrea Lee Frump的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Andrea Lee Frump', 18)}}的其他基金
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:
10503725 - 财政年份:2022
- 资助金额:
$ 78万 - 项目类别: