# Serotonin-2B receptor in hypertrophic cardiomyopathy

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
The overall objective of this proposal is to elucidate the cellular mechanism and therapeutic potential of targeting
the serotonin-2B receptor (5-HT2B) to attenuate fibrosis in hypertrophic cardiomyopathy (HCM). HCM is the most
common monogenic heart disease and the most common cause of sudden death in young adults. A hallmark of
this disease is myocardial fibrosis, an early manifestation of HCM defined as pathological remodeling that leads
to heart wall stiffening and diastolic dysfunction. Due to the lack of knowledge on HCM disease emergence and
progression, there is an unmet need to identify new pathways and therapeutic opportunities targeting
fibrosis in HCM. Cardiac fibroblasts (CFs) are the primary cell type that contribute to fibrosis, as their function
to preserve the myocytes’ surrounding environment by degrading and synthesizing the extracellular matrix can
lead to pathological remodeling of the myocardium. Previous studies have antagonized 5-HT2B in
cardiopulmonary diseases and demonstrated a decrease in fibrosis; in a mouse model of myocardial infarction,
5-HT2B antagonism decreased both the fibrotic scar size and number of isotropic collagen fibers in the
myocardium, preventing the fibrotic remodeling process and preserving systolic and diastolic function. Our
preliminary data shows an increase in 5-HT2B expression in HCM patients and a correlation between 5-HT2B and
ANP, a marker of cardiac hypertrophy. In our hands, the 403/+ mouse model of familial HCM confirms an
increase in 5-HT2B expression and pro-fibrotic markers. Therefore, we hypothesize that ablating 5-HT2B
activity will attenuate fibrosis in HCM. To investigate this hypothesis, the following aims will be addressed. 1)
Clarify the CFs vs. cardiomyocytes contribution to attenuation of fibrosis in HCM through global and CF-specific
genetic ablation of 5-HT2B. This will be tested through the creation of two mouse models that provide both global
and CF-specific genetic deletion of 5-HT2B. 2) Test the therapeutic efficacy of 5-HT2B antagonism and subsequent
mechanical characterization of the cell type responsible for 5-HT2B – mediated fibrotic remodeling in HCM.
Collaboration with Dr. Craig Lindsley has led to the discovery of two novel compounds that are highly specific
for 5-HT2B and are systemically restricted from entering the brain. Following 5-HT2B antagonism, CFs will be
isolated and mechanically characterized for their proliferative, contractile, and migratory capabilities. The
training received throughout this fellowship will enable the candidate to conduct a successful project
that will enhance our understanding of the underlying pathology and therapeutic potential of 5-HT2B
antagonism in hypertrophic cardiomyopathy.

## Key facts

- **NIH application ID:** 10826279
- **Project number:** 1F31HL172640-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** William Bryan Livingston
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10826279

## Citation

> US National Institutes of Health, RePORTER application 10826279, Serotonin-2B receptor in hypertrophic cardiomyopathy (1F31HL172640-01). Retrieved via AI Analytics 2026-07-25 from https://api.ai-analytics.org/grant/nih/10826279. Licensed CC0.

---

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