Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension
Open accessAbstract
Background Substance P is a sensory nerve neuropeptide located near coronary vessels in the heart. Therefore, substance P may be one of the first mediators released in the heart in response to hypertension, and can contribute to adverse myocardial remodeling via interactions with the neurokinin-1 receptor. We asked: 1) whether substance P promoted cardiac hypertrophy, including the expression of fetal genes known to be re-expressed during pathological hypertrophy; and 2) the extent to which substance P regulated collagen production and fibrosis.Methods and results Spontaneously hypertensive rats (SHR) were treated with the neurokinin-1 receptor antagonist L732138 (5mg/kg/d) from 8 to 24 weeks of age. Age-matched WKY served as controls. The gene encoding substance P, TAC1, was up-regulated as blood pressure increased in SHR. Fetal gene expression by cardiomyocytes was increased in SHR and was prevented by L732138. Cardiac fibrosis also occurred in the SHR and was prevented by L732138. Endothelin-1 was up-regulated in the SHR and this was prevented by L732138. In isolated cardiac fibroblasts, substance P transiently up-regulated several genes related to cell-cell adhesion, cell-matrix adhesion, and extracellular matrix regulation, however, no changes in fibroblast function were observed.Conclusions Substance P activation of the neurokinin-1 receptor induced expression of fetal genes related to pathological hypertrophy in the hypertensive heart. Additionally, activation of the neurokinin-1 receptor was critical to the development of cardiac fibrosis. Since no functional changes were induced in isolated cardiac fibroblasts by substance P, we conclude that substance P mediates fibrosis via up-regulation of endothelin-1.
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SP plays an important role in cardiac fibrosis in response to hypertension.
“SP plays an important role in cardiac fibrosis in response to hypertension80.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [80]
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- Authors
- Dehlin, H. M., Manteufel, E. J., Monroe, A. L., Reimer, M. H., & Levick, S. P.
- Affiliations
- Medical College of Wisconsin (US)
- Corresponding author
- Levick, Scott P.
- ORCID
- Levick, Scott P.
- Venue
- International Journal of Cardiology
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 168
- Issue
- 5
- Pages
- 4643-4651
- ISSN
- 0167-5273 (ISSN-L)
- PMC
- PMC4043399
- OpenAlex
- W2074505827
- Cited by
- 55
- References
- 39
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 2 · 2019: 11 · 2018: 8 · 2017: 4 · 2016: 2 · 2015: 2 · 2014: 6
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- International Journal of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R00HL093215, T32HL007792)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- substance P, neurokinin-1 receptor, hypertension, cardiac remodeling, cardiac hypertrophy, myocardial fibrosis, endothelin-1, fetal gene expression, TAC1, spontaneously hypertensive rats, cardiac fibroblasts, extracellular matrix
- MeSH terms
- Animals, Disease Models, Animal, Female, Heart Ventricles, Hypertension, Pregnancy, Pregnancy, Animal, Rats, Inbred SHR, Rats, Inbred WKY, RNA, Messenger, Substance P, Polymerase Chain Reaction, Ventricular Function, Left, Receptors, Neurokinin-1, Gene Expression Regulation, Developmental, Ventricular Remodeling, Myocytes, Cardiac, Rats
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