Abstract
Cardiac fibrosis is a scarring event that occurs in the myocardium in response to multiple cardiovascular disorders, such as acute myocardial infarction (AMI), ischemic cardiomyopathy, dilated cardiomyopathy, hypertensive heart disease, inflammatory heart disease, diabetic cardiomyopathy, and aortic stenosis. Fibrotic remodeling is mainly sustained by the differentiation of fibroblasts into myofibroblasts, which synthesize and secrete most of the extracellular matrix (ECM) proteins. An increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) in cardiac fibroblasts is emerging as a critical mediator of the fibrogenic signaling cascade. Herein, we review the mechanisms that may shape intracellular Ca(2+) signals involved in fibroblast transdifferentiation into myofibroblasts. We focus our attention on the functional interplay between inositol-1,4,5-trisphosphate (InsP(3)) receptors (InsP(3)Rs) and store-operated Ca(2+) entry (SOCE). In accordance with this, InsP(3)Rs and SOCE drive the Ca(2+) response elicited by G(q)-protein coupled receptors (G(q)PCRs) that promote fibrotic remodeling. Then, we describe the additional mechanisms that sustain extracellular Ca(2+) entry, including receptor-operated Ca(2+) entry (ROCE), P2X receptors, Transient Receptor Potential (TRP) channels, and Piezo1 channels. In parallel, we discuss the pharmacological manipulation of the Ca(2+) handling machinery as a promising approach to mitigate or reverse fibrotic remodeling in cardiac disorders.