# A Pathogenic Role for Natriuretic Peptide Receptor-C in Pulmonary Hypertension and Heart Failure with Preserved Ejection Fraction

> **NIH NIH K08** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $158,436

## Abstract

Project Summary/Abstract:
Heart failure with preserved ejection fraction (HFpEF) affects over 3 million people nationwide and carries a
75% 5-year mortality. 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 mentor, Dr. 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 PGC1α. 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 R01 submission.

## Key facts

- **NIH application ID:** 10463813
- **Project number:** 5K08HL153956-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Vineet Agrawal
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $158,436
- **Award type:** 5
- **Project period:** 2021-08-10 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463813

## Citation

> US National Institutes of Health, RePORTER application 10463813, A Pathogenic Role for Natriuretic Peptide Receptor-C in Pulmonary Hypertension and Heart Failure with Preserved Ejection Fraction (5K08HL153956-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10463813. Licensed CC0.

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