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Principal Investigator: Andrea Lee Frump
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2023
Award: $780,019
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <ACE Inhibitors><ACE2><APLN><APLN gene><Agonist><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Blood Vessels><Body Tissues><CD143 Antigens><Carboxycathepsin><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Clinical><Cor pulmonale><Data><Death><Development><Dipeptidyl Peptidase A><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Dysfunction><Endothelial Cells><Experimental Models><Functional disorder><Goals><Heart><Heart Muscle Cells><Heart myocyte><Human><Impairment><Industry><Intracellular Communication and Signaling><Kininase A><Kininase II><Kininase II Antagonists><Kininase II Inhibitors><Link><Lung><Lung Respiratory System><Mediating><Mediator><Mission><Modeling><Modern Man><Molecular><NHLBI><National Heart, Lung, and Blood Institute><Nuclear><Nuclear Receptors><Oral><Outcome><Pathway interactions><Patient Rights><Patients><Peptides><Peptidyl-Dipeptidase A><Physiopathology><Public Health><Publishing><Pulmonary Artery><Pulmonary Heart Disease><Pulmonary Heart Disorder><Pulmonary Hypertension><Pulmonary Vascular Resistance><Pulmonary artery structure><Receptor Protein><Renin-Angiotensin-Aldosterone System><Research><Right Ventricular Function><Rodent Model><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Testing><Therapeutically Targetable><Tissues><Vasodilatation><Vasodilation><Vasorelaxation><Ventricular><Work><angiogenesis><angiotensin converting enzyme 2><angiotensin converting enzyme II><apelin><biological signal transduction><cardiac function><cardiomyocyte><cardiopulmonary disease><cardiopulmonary disorder><developmental><function of the heart><heart function><iPS><iPSC><iPSCs><improved><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><interest><lung vascular remodeling><lung vasoconstriction><mortality><novel><pathophysiology><pathway><prevent><preventing><protective effect><pulmonary><pulmonary arterial endothelial cell><pulmonary artery endothelial cell><pulmonary vascular constriction><pulmonary vascular remodeling><pulmonary vasoconstriction><receptor><receptor-mediated signaling><right heart failure><right sided heart failure><right ventricle failure><right ventricle remodeling><right ventricular failure><right ventricular heart failure><right ventricular remodeling><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><treatment strategy><vascular>