Ca(2+) Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Cardiac fibrosis is the excessive deposition of extracellular matrix proteins by cardiac fibroblasts and myofibroblasts, and is a hallmark feature of most heart diseases, including arrhythmia, hypertrophy, and heart failure. This maladaptive process occurs in response to a variety of stimuli, including myocardial injury, inflammation, and mechanical overload. There are multiple signaling pathways and various cell types that influence the fibrogenesis cascade. Fibroblasts and myofibroblasts are central effectors. Although it is clear that Ca(2+) signaling plays a vital role in this pathological process, what contributes to Ca(2+) signaling in fibroblasts and myofibroblasts is still not wholly understood, chiefly because of the large and diverse number of receptors, transporters, and ion channels that influence intracellular Ca(2+) signaling. Intracellular Ca(2+) signals are generated by Ca(2+) release from intracellular Ca(2+) stores and by Ca(2+) entry through a multitude of Ca(2+)-permeable ion channels in the plasma membrane. Over the past decade, the transient receptor potential (TRP) channels have emerged as one of the most important families of ion channels mediating Ca(2+) signaling in cardiac fibroblasts. TRP channels are a superfamily of non-voltage-gated, Ca(2+)-permeable non-selective cation channels. Their ability to respond to various stimulating cues makes TRP channels effective sensors of the many different pathophysiological events that stimulate cardiac fibrogenesis. This review focuses on the mechanisms of Ca(2+) signaling in fibroblast differentiation and fibrosis-associated heart diseases and will highlight recent advances in the understanding of the roles that TRP and other Ca(2+)-permeable channels play in cardiac fibrosis.