Faculty Collaboration Database

Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells. Cardiovasc Res 2011 Dec 01;92(3):420-9

Date

09/13/2011

Pubmed ID

21908647

Pubmed Central ID

PMC3211974

DOI

10.1093/cvr/cvr244

Scopus ID

2-s2.0-81055147153 (requires institutional sign-in at Scopus site)   65 Citations

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.

Author List

Meléndez GC, Li J, Law BA, Janicki JS, Supowit SC, Levick SP

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Cell Degranulation
Collagen
Disease Models, Animal
Heart Failure
In Situ Nick-End Labeling
Male
Mast Cells
Matrix Metalloproteinases
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardium
Neurokinin A
Neurokinin-1 Receptor Antagonists
Rats
Rats, Sprague-Dawley
Receptors, Neurokinin-1
Substance P
Time Factors
Tryptophan
Tumor Necrosis Factor-alpha
Ultrasonography
Ventricular Remodeling