Regulation of Cardiac Mast Cell Maturation and Function by the Neurokinin-1 Receptor in the Fibrotic Heart

Abstract

Cardiac fibrosis is an underlying cause of diastolic dysfunction, contributing to heart failure. Substance P (SP) activation of the neurokinin-1 receptor (NK-1R) contributes to cardiac fibrosis in hypertension. However, based on in vitro experiments, this does not appear to be via direct activation of cardiac fibroblasts. While numerous cells could mediate the fibrotic effects of SP, herein, we investigate mast cells (MC) as a mechanism mediating the fibrotic actions of SP, since MCs are known to play a role in cardiac fibrosis and respond to SP. Spontaneously hypertensive rats (SHR) were treated with the NK-1R antagonist L732138 (5 mg/kg/d) from 8 to 12 weeks of age. L732138 prevented increased MC maturation of resident immature MCs. NK-1R blockade also prevented increased cardiac MC maturation in angiotensin II-infused mice. MC-deficient mice were used to test the importance of MC NK-1Rs to MC activation. MC-deficient mice administered angiotensin II did not develop fibrosis; MC-deficient mice reconstituted with MCs did develop fibrosis. MC-deficient mice reconstituted with MCs lacking the NK-1R also developed fibrosis, indicating that NK-1Rs are not required for MC activation in this setting. In conclusion, the NK-1R causes MC maturation, however, other stimuli are required to activate MCs to cause fibrosis.

The Histamine 3 Receptor Is Expressed in the Heart and Its Activation Opposes Adverse Cardiac Remodeling in the Angiotensin II Mouse Model

“…In additional support of this finding, both mast cell and macrophage numbers remained elevated in the heart after A331440 treatment. Both mast cells and macrophages are important contributors to the cardiac fibrosis process [ 1 , 2 , 3 , 4 , 5 , 8 , 9 , 22 , 23 , 24 ].…”

“…Adverse myocardial remodeling, including cardiac fibrosis and cardiomyocyte hypertrophy, can lead to LV diastolic and systolic dysfunction and eventual heart failure. There is substantial evidence to support a contribution of mast cells to cardiac fibrosis in particular, through the release of pre-stored mediators such as the proteases tryptase and chymase [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Histamine, which is derived from the amino acid histidine via decarboxylation by the enzyme histidine decarboxylase, is another pre-stored mast cell product.…”

Neurokinin-1 Receptor as a potential drug target for COVID-19 treatment

“…It may lead to fibrosis in hypertensive rat heart [55] which is an underlying mechanism for heart failure due to diastolic dysfunction. It increases the number of mature mast cells in hypertensive heart by activating and releasing more stem cell factor (SCF) [56] . It regulates the cardiac frequency, BP, stress response mechanisms, angiogenesis, pain transmission and inflammation [57] .…”

Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review

“…Current evidence also suggests that SP and NK-1R are viable targets for interventions that specifically address various dermatologic conditions, and a selective NK1 receptor antagonist might be a viable treatment option for patients with psoriatic pruritus [64,65]. SP/NK-1R is essential to cause increased numbers of mature MCs in the hypertensive heart, although NK-1R is not required for the activation of cardiac MCs in vivo [66]. However, mounting evidence currently suggests that SP activates MCs primarily through the G protein-coupled, Masrelated gene X2 receptor (MrgprX2) [67,68].…”