title: Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension.
abstract: 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.
  
  
  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.
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, United States; Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, United States.
authors: Heather M
authors: HM
authors: Dehlin
authors: Edward J
authors: EJ
authors: Manteufel
authors: Andrew L
authors: AL
authors: Monroe
authors: Michael H
authors: MH
authors: Reimer
authors: Scott P
authors: SP
authors: Levick
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011270:Pregnancy, Animal; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis / Q000235:genetics*; D013373:Substance P / Q000096:biosynthesis / Q000235:genetics*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D013373:Substance P
keywords: Cardiac fibroblast; Fetal genes; Fibrosis; Hypertrophy; Substance P
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