Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells.

Abstract

AIMS:

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.

METHODS AND 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: Giselle C Meléndez, Jianping Li, Brittany A Law, Joseph S Janicki, Scott C Supowit, Scott P Levick
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 92 Issue 3 Pg. 420-9 (Dec 01 2011) ISSN: 1755-3245 [Electronic] England
• PMID: 21908647 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Neurokinin-1 Receptor Antagonists
• Receptors, Neurokinin-1
• Tumor Necrosis Factor-alpha
• 3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan
• Substance P
• Neurokinin A
• Tryptophan
• Collagen
• Matrix Metalloproteinases

Topics

• Animals
• Apoptosis
• Cell Degranulation
• Collagen (metabolism)
• Disease Models, Animal
• Heart Failure (diagnostic imaging, genetics, metabolism, pathology)
• In Situ Nick-End Labeling
• Male
• Mast Cells (metabolism, pathology)
• Matrix Metalloproteinases (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (metabolism, pathology)
• Neurokinin A (genetics, metabolism)
• Neurokinin-1 Receptor Antagonists
• Rats
• Rats, Sprague-Dawley
• Receptors, Neurokinin-1 (metabolism)
• Substance P (deficiency, genetics, metabolism)
• Time Factors
• Tryptophan (analogs & derivatives, pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• Ultrasonography
• Ventricular Remodeling