# Substance P: A central mediator of cardiac fibrosis and diastolic dysfunction

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $341,260

## Abstract

We recently demonstrated that the sensory nerve neuropeptide substance P (SP) is required for the
development of cardiac fibrosis in response to elevations in myocardial stress, specifically pressure overload
(PO). Due to its localization to sensory nerves projecting to coronary arteries, SP is likely one of the first
mediators released in response to changes in coronary pressure/flow. We believe that this places SP up-
stream of multiple pro-fibrotic cascades, and we have identified several cell-specific effects initiated by SP in
response to PO. Therefore, targeting SP holds real therapeutic potential, however, dissection of these cell-
specific pathways is firstly required. What makes SP an even more attractive therapeutic target is the existence
of two isoforms of its receptor, the neurokinin-1 receptor (NK-1R). We believe that the full length NK-1R
mediates the physiological actions of SP, while the truncated isoform mediates the pro-fibrotic effects. Thus, it
may be possible to selectively target the adverse effects of SP, while leaving the physiological actions intact.
This proposal will examine the role of these NK-1R isoforms in mediating the cell-specific actions of SP on
multiple pathways involved in cardiac fibrosis: 1) focal cardiomyocyte necrosis and the subsequent
macrophage response; 2) SP/endothelin-1 interactions at the level of the cardiac fibroblast; and 3) mast cell-
specific proteases. Our overall hypothesis is that SP acts via the truncated NK-1R to modulate cell-specific
molecular pathways to promote cardiac fibrosis and diastolic dysfunction. Specific aim 1 will examine the
extent to which SP activation of the NK-1R on sympathetic nerves initiates focal cardiomyocyte necrosis, a
known stimulus for fibrosis. Further, the contribution to fibrosis of SP activated macrophages in response to
focal necrosis will also be examined. Specific aim 2 will examine the synergistic actions of SP and endothelin-1
on cardiac fibroblast phenotype and function. This includes investigating truncated NK-1R activation of the
membrane type 1 matrix metalloproteinase/TGF-β1 pathway in vitro. Myofibroblast-specific NK-1R-deficient
mice will be used to examine the role of myofibroblast-specific NK-1Rs in vivo under conditions of PO. Specific
aim 3 will identify the importance of mast cell-specific NK-1Rs in mediating the release of mast cell-derived
pro-fibrotic molecules including tryptase and chymase. This proposal is significant and innovative because it
will establish a neuropeptide as a mediator of cardiac fibrosis and diastolic dysfunction, as well as identifying
cell-specific mechanisms by which SP promotes fibrosis. Of high significance is the existence of the two NK-1R
isoforms, of which we believe the truncated isoform mediates the pro-fibrotic actions of SP. Thus, this proposal
will identify a unique, actionable therapeutic target for diastolic dysfunction since antagonists, biologics, or
gene therapy approaches specific to the truncate...

## Key facts

- **NIH application ID:** 9948002
- **Project number:** 5R01HL132908-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** WILLIAM BRYSON CAMPBELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $341,260
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948002

## Citation

> US National Institutes of Health, RePORTER application 9948002, Substance P: A central mediator of cardiac fibrosis and diastolic dysfunction (5R01HL132908-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948002. Licensed CC0.

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