# Cardiomyocyte TRPV4 and cardiac dysfunction following ischemia-reperfusion in the aged heart.

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2020 · $375,725

## Abstract

Project Summary/Abstract
Advancing age is the primary risk factor for coronary artery disease and myocardial infarction (MI). A major cause
of arrhythmia and tissue damage following MI is reperfusion injury (ischemia-reperfusion or I-R) which associates
with excessive calcium concentration within cardiomyocytes, a process termed calcium overload. Our laboratory
recently showed that the transient receptor potential vanilloid, member 4 (TRPV4) cation channel is highly
expressed within cardiomyocytes of the aged (but not young) heart and contributes to intracellular calcium
overload following hypoosmotic stress. Osmotic changes in cardiac tissue are pronounced during I-R, and
reperfusion associates with substantial hypoosmotic stress on cardiomyocytes. Therefore, this proposal tests
the central hypothesis that TRPV4 contributes to calcium overload and cardiac dysfunction following I-R. To test
this hypothesis we utilize young (3-6 months, with low TRPV4 expression) and aged (24-26 months, with high
TRPV4 expression) C576BL/6 mice, young cardiomyocyte-specific TRPV4 transgenic mice (“overexpressors”
with high TRPV4 expression), and aged TRPV4 knock-out mice (with no TRPV4 expression). To complement
this genetic approach we also utilize a pharmacological approach with specific antagonists of TRPV4. Specific
Aim 1 tests the hypothesis that TRPV4 produces cardiomyocyte calcium overload, excessive contractility, and
arrhythmia following I-R. Isolated cardiomyocytes subjected to simulated I-R (combined metabolic and osmotic
stress) will be used to examine the effect of TRPV4 on calcium signaling modalities using high-resolution
confocal fluorescence microscopy. Similarly, transgenic mouse hearts which encode the GCaMP6f calcium
sensor will be subjected to ex vivo I-R with pro-arrhythmic calcium signaling monitored within the intact organ.
Langendorff-perfused hearts will be utilized to test the role of TRPV4 on contractility and arrhythmia following I-
R. Specific Aim 2 tests the hypothesis that TRPV4 contributes to cardiomyocyte death, tissue damage, and
adverse cardiac remodeling following I-R. Fluorescence imaging approaches of mitochondrial membrane
potential and plasma membrane integrity will elucidate the role of TRPV4 on cardiomyocyte dysfunction and
death in real time following simulated I-R or in ex vivo perfused hearts following I-R. Translational studies using
orally bioavailable TRPV4 inhibitors will be used to examine the role of TRPV4 in adverse cardiac remodeling
and tissue damage following I-R in vivo. The goal of this project is to rigorously examine the role of the TRPV4
ion channel in cardiac dysfunction and tissue damage following I-R, with the long-term goal of translating our
research findings into new treatments for aged individuals following MI.

## Key facts

- **NIH application ID:** 9852463
- **Project number:** 5R01HL136292-04
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Timothy Lee Domeier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,725
- **Award type:** 5
- **Project period:** 2017-03-03 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852463

## Citation

> US National Institutes of Health, RePORTER application 9852463, Cardiomyocyte TRPV4 and cardiac dysfunction following ischemia-reperfusion in the aged heart. (5R01HL136292-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852463. Licensed CC0.

---

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