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Determining the Contribution of Mast Cell‐specific Neurokinin‐1 Receptors in Pressure Overload‐Induced Cardiac Fibrosis

Substance P (SP) and mast cells (MCs) both play a detrimental role in initiating myocardial remodeling, including fibrosis, in response to pressure overload. However, it is not known whether MC activation is an underlying mechanism mediating the effects of SP in this setting. We sought to determine whether SP and its cognate receptor, the neurokinin‐1 receptor (NK‐1R), regulate MC function and whether this is a mechanism underlying the pro‐fibrotic actions of SP. Administration of the NK‐1R antagonist, L732138 to spontaneous hypertensive rats (SHR) reduced cardiac MC density by reducing levels of stem cell factor (SCF), which promotes MC proliferation and maturation. SP treatment of bone marrow derived mast cells (BMMCs), as a model of cardiac MCs, showed no change in c‐kit levels (SCF receptor) or apoptosis, ruling out the possibility of SP/NK‐1R in regulating MC number through increasing the response to SCF or via altering apoptosis. Interestingly, SP activation of the NK‐1R does not activate MCs since conditioned media from SP treated MCs had no effect on collagen synthesis by cultured fibroblasts, and reconstitution of MC‐deficient mice with MCs lacking the NK‐1R did not reduce cardiac fibrosis in angiotensin II‐infused mice. Further, whilst SCF is important in MC proliferation, it also does not activate MCs as there was no increase in cardiac collagen in SCF injected mice. In conclusion, SP activation of the NK‐1R increases MC density in the overloaded heart via production of SCF, however, neither SP nor SCF activate MCs in this setting. Thus, the stimulus activating MCs in the setting of cardiac fibrosis is still unknown.