Substance P-mediated cardiac mast cell activation: An in vitro study

Abstract

The neuropeptide substance P can induce degranulation of cardiac mast cells at high concentrations. Herein, we seek to further understand substance P activation of cardiac mast cells in the context of other neuropeptides as well as modulation by non-neuropeptides. This is important given the increasingly recognized role of both cardiac mast cells and substance P in adverse cardiac remodeling. To address this, we isolated cardiac mast cells and compared their response to substance P as well as other members from the tachykinin family of peptides, including neurokinin A and hemokinin-1. We also tested the ability of other factors to manipulate the cardiac mast cell response to substance P. We found that while neurokinin A did not induce cardiac mast cell degranulation, both substance P and hemokinin-1 induced a concentration-dependent release of histamine; the maximal response to hemokinin-1 was greater than to substance P. Neurokinin-1 receptor blockade prevented substance P-induced histamine release, while only partially attenuating hemokinin-1-induced histamine release. The antioxidant N-acetylcysteine attenuated histamine release in response to hemokinin-1 and had no effect on substance P-induced histamine release. Selective PPAR-γ agonists attenuated histamine release in response to substance P. These data indicate that substance P activates cardiac mast cells via the neurokinin-1 receptor, and that the activation response is different to other tachykinins. That the response to substance P is receptor mediated and can be modulated by activation of other receptors (PPAR-γ), argues that substance P activation of cardiac mast cells has potential biological significance.