R01HL164791

The emerging role of apelin, RAAS, and ACE2 crosstalk in pulmonary hypertension - 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 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-CMs), 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 adaptive 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.

Trustees Of Indiana University

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Indianapolis, Indiana 462025188 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 330% from $706,423 to $3,037,281.