Autocrine Signaling in Cardiac Remodeling: A Rich Source of Therapeutic Targets

Abstract The myocardium consists of different cell types, of which endothelial cells, cardiomyocytes, and fibroblasts are the most abundant. Communication between these different cell types, also called paracrine signaling, is essential for normal cardiac function, but also important in cardiac remodeling and heart failure. Systematic studies on the expression of ligands and their corresponding receptors in different cell types showed that for 60% of the expressed ligands in a particular cell, the receptor is also expressed. The fact that many ligand‐receptor pairs are present in most cells, including the major cell types in the heart, indicates that autocrine signaling is a widespread phenomenon. Autocrine signaling in cardiac remodeling and heart failure is involved in all pathophysiological mechanisms generally observed: hypertrophy, fibrosis, angiogenesis, cell survival, and inflammation. Herein, we review ligand‐receptor pairs present in the major cardiac cell types based on RNA‐sequencing expression databases, and we review current literature on extracellular signaling proteins with an autocrine function in the heart; these include C‐type natriuretic peptide, fibroblast growth factors 2, F21, and 23, macrophage migration inhibitory factor, heparin binding–epidermal growth factor, angiopoietin‐like protein 2, leptin, adiponectin, follistatin‐like 1, apelin, neuregulin 1, vascular endothelial growth factor, transforming growth factor β, wingless‐type integration site family, member 1‐induced secreted protein‐1, interleukin 11, connective tissue growth factor/cellular communication network factor, and calcitonin gene‒related peptide. The large number of autocrine signaling factors that have been studied in the literature supports the concept that autocrine signaling is an essential part of myocardial biology and disease.