# A Pathogenic Role for the Natriuretic Peptide Clearance Receptor in Heart Failure with Preserved Ejection Fraction.

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

PROJECT SUMMARY
Heart failure with preserved ejection fraction (HFpEF) affects almost 2.5% of all US Veterans, and it
contributes to nearly 1 in 14 deaths in Veterans. Unlike other forms of heart failure, there are currently no
treatment options for HFpEF that reduce mortality. A common cause of morbidity and mortality in HFpEF is
right ventricular (RV) failure, and there are currently no therapies directly targeting RV failure in heart failure.
Regardless of the cause, studies have shown that the failing RV undergoes a metabolic shift characterized by
decreased utilization of fatty acid oxidation for energy generation and increased mitochondrial dysfunction.
While restoring fatty acid oxidation and mitochondrial function are thought to be beneficial, there are currently
no therapies that can successfully do so in the failing RV. The goal of the proposal is to support the career
development of Dr. Vineet Agrawal by providing him the training, mentorship, and resources to pursue a career
in identifying mechanisms by which obesity and metabolic dysfunction fundamentally alter RV metabolism to
promote failure, and secondarily identify viable therapies to improve outcomes in a patient population that
currently has none. This work is supported by primary mentors, Drs. Julie Bastarache and Anna Hemnes, and
a complementary research advisory committee. Dr. Agrawal will leverage their combined mentorship to study
the role of a novel therapeutic target, natriuretic peptide clearance receptor NPRC, in the treatment of obesity-
induced HFpEF. The central hypothesis of this proposal is that increased NPRC expression in the HFpEF RV
results in RV failure through impaired mitochondrial biogenesis and fatty acid oxidation. This central hypothesis
will be tested in two specific aims that will test the following hypotheses: (1) that knockdown of NPRC in a
model of obesity-induced HFpEF prevents and reverses RV failure by restoring fatty acid oxidation and
mitochondrial biogenesis, and (2) NPRC directly inhibits mitochondrial biogenesis and fatty acid oxidation in
vitro through cAMP and cGMP-mediated regulation of PGC1a. This proposal will utilize a novel transgenic
mouse in which NPRC can inducibly be knocked out to study the role of NPRC in vivo, and CRISPR edited
human induced pluripotent stem cells and H9C2 cardiomyocyte-like cells to study the role of NPRC in
modulating cardiomyocyte function in vitro. Through the studies proposed to test the hypotheses above, Dr.
Agrawal will also accomplish the following career development and training objectives to: (1) master
techniques to study mitochondrial function and metabolism of tissue and cells, (2) master techniques to
generate and differentiate human induced pluripotent stem cells and cardiomyocytes (hiPSCs), (3) master
techniques in gene editing in vitro, and (4) refine professional development and communication skills to
achieve goals of academic progress, effective communication, and successful VA Merit submis...

## Key facts

- **NIH application ID:** 10765668
- **Project number:** 5IK2BX005828-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Vineet Agrawal
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-03-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765668

## Citation

> US National Institutes of Health, RePORTER application 10765668, A Pathogenic Role for the Natriuretic Peptide Clearance Receptor in Heart Failure with Preserved Ejection Fraction. (5IK2BX005828-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10765668. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*