Substance P in heart failure: The good and the bad

Abstract

The tachykinin, substance P, is found primarily in sensory nerves. In the heart, substance P-containing nerve fibers are often found surrounding coronary vessels, making them ideally situated to sense changes in the myocardial environment. Recent studies in rodents have identified substance P as having dual roles in the heart, depending on disease etiology and/or timing. Thus far, these studies indicate that substance P may be protective acutely following ischemia-reperfusion, but damaging long-term in non-ischemic induced remodeling and heart failure. Sensory nerves may be at the apex of the cascade of events leading to heart failure, therefore, they make a promising potential therapeutic target that warrants increased investigation.

Introduction

Substance P is from the tachykinin family of sensory nerve neuropeptides. The other classic members of this family are neurokinin A (NKA) and neurokinin B (NKB). While NKB is encoded for by its own gene (TAC2) and is restricted to the central nervous system, substance P and NKA are both encoded by the TAC1 gene and are found in the central nervous system and peripheral afferent sensory neurons [1], [2]. The TAC1 gene expresses pre-mRNA that can generate four mRNA isoforms (α, β, γ, and δ). All four isoforms give rise to substance P, whereas only the β and γ isoforms encode for NKA. This means that substance P can be expressed without NKA, however, NKA will always be accompanied by substance P. However, since the β and γ isoforms appear to be the most common, substance P and NKA will often be synthesized, stored, and released together [1]. Substance P acts primarily through the neurokinin (NK)-1 receptor, while NKA exerts its effects via the NK-2 receptor, although there is some overlap between the two [3]. The actions of tachykinins are many, but include smooth muscle contraction, vasodilation, nociception, and modulation of inflammatory/immune cell function [4], [5], [6], [7], [8]. Substance P and NKA have long been known to have negative inotropic and chronotropic effects on the normal heart [9], [10], but it is only recently that we are beginning to consider that sensory nerve neuropeptides may have key roles in regulating adverse myocardial remodeling and the subsequent development of heart failure. Outside of the aforementioned effects on heart rate and contraction, little has been published relating to NKA and myocardial remodeling. Accordingly, this article will focus on substance P. What makes substance P so interesting is that recent experimental studies have revealed two sides to this neuropeptide in myocardial remodeling and heart failure; the good and the bad. Accordingly, the purpose of this review is to draw attention to the role of substance P in adverse myocardial remodeling and heart failure, since to this point in time it's role in these events have not been studied in detail. As such, this review will: 1) describe the localization of substance P within the myocardium; 2) describe the beneficial role of substance P acutely following ischemia reperfusion; 3) describe the detrimental role of substance P in long-term remodeling of the heart; 4) describe the direct effects of substance P on cardiomyocytes, cardiac fibroblasts, and cardiac inflammatory cells; and 5) discuss the clinical implications of substance P in the heart.