title: Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells.
abstract: OBJECTIVE
  Substance P and neurokinin A (NKA) are sensory nerve neuropeptides encoded by the TAC1 gene. Substance P is a mast cell secretagogue and mast cells are known to play a role in adverse myocardial remodelling. Therefore, we wondered whether substance P and/or NKA modulates myocardial remodelling via a mast cell-mediated mechanism.
  
  
  RESULTS
  Volume overload was induced by aortocaval fistula in TAC1(-/-) mice and their respective wild types. Left ventricular internal diameter of wild-type (WT) fistulas increased by 31.9%; this was prevented in TAC1(-/-) mice (4.2%). Matrix metalloproteinase (MMP) activity was significantly increased in WT fistula mice and was prevented in TAC1(-/-) mice. Myocardial collagen volume fraction was decreased in WT fistula mice; this collagen degradation was not observed in the TAC1(-/-) group. There were no significant differences between any groups in tumour necrosis factor (TNF)-α or cell death. Cardiac mast cells were isolated from rat hearts and stimulated with substance P or NKA. We found that these cells degranulated only to substance P, via the neurokinin-1 receptor. To determine the effect of substance P on mast cells in vivo, volume overload was created in Sprague-Dawley rats treated with the NK-1 receptor antagonist L732138 (5 mg/kg/day) for a period of 3 days. L732138 prevented: (i) increases in cardiac mast cell density; (ii) increased myocardial TNF-α; and (iii) collagen degradation.
  
  
  CONCLUSIONS
  Our studies suggest that substance P may be important in mediating adverse myocardial remodelling secondary to volume overload by activating cardiac mast cells, leading to increased TNF-α and MMP activation with subsequent degradation of the extracellular matrix.
authors: Cell Biology and Anatomy, School of Medicine,  University of South Carolina, Columbia, SC 29208,  USA.
authors: Giselle C
authors: GC
authors: Meléndez
authors: Jianping
authors: J
authors: Li
authors: Brittany A
authors: BA
authors: Law
authors: Joseph S
authors: JS
authors: Janicki
authors: Scott C
authors: SC
authors: Supowit
authors: Scott P
authors: SP
authors: Levick
mesh_terms: D000818:Animals; D017209:Apoptosis; D015550:Cell Degranulation; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D008297:Male; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D015288:Neurokinin A / Q000235:genetics / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014463:Ultrasonography; D020257:Ventricular Remodeling
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D014409:Tumor Necrosis Factor-alpha; C086089:3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan; D013373:Substance P; D015288:Neurokinin A; D014364:Tryptophan; D003094:Collagen; D020782:Matrix Metalloproteinases