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

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $706,423

## Abstract

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 pathw...

## Key facts

- **NIH application ID:** 10503725
- **Project number:** 1R01HL164791-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Andrea Lee Frump
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $706,423
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10503725

## Citation

> US National Institutes of Health, RePORTER application 10503725, The emerging role of apelin, RAAS, and ACE2 crosstalk in pulmonary hypertension (1R01HL164791-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10503725. Licensed CC0.

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