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-?1 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 truncated NK-1R could be developed.

Public Health Relevance

Under conditions of hemodynamic stress, the heart develops fibrosis, which contributes to the inability of the heart to relax properly and its eventual failure. Substance P is a neuropeptide that has been identified as central to this process. The current proposal will explore the mechanisms by which substance P promotes fibrosis, including actions on fibroblasts and mast cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132908-03
Application #
9725769
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2017-09-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Pharmacology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Levick, Scott P; Widiapradja, Alexander (2018) Mast Cells: Key Contributors to Cardiac Fibrosis. Int J Mol Sci 19:
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Widiapradja, Alexander; Chunduri, Prasad; Levick, Scott P (2017) The role of neuropeptides in adverse myocardial remodeling and heart failure. Cell Mol Life Sci 74:2019-2038