Cardiac fibroblasts as sentinel cells in cardiac tissue: Receptors, signaling pathways and cellular functions.

Cardiac fibroblasts (CF) not only modulate extracellular matrix (ECM) proteins homeostasis, but also respond to chemical and mechanical signals. CF express a variety of receptors through which they modulate the proliferation/cell death, autophagy, adhesion, migration, turnover of ECM, expression of cytokines, chemokines, growth factors and differentiation into cardiac myofibroblasts (CMF). Differentiation of CF to CMF involves changes in the expression levels of various receptors, as well as, changes in cell phenotype and their associated functions. CF and CMF express the β2-adrenergic receptor, and its stimulation activates PKA and EPAC proteins, which differentially modulate the CF and CMF functions mentioned above. CF and CMF also express different levels of Angiotensin II receptors, in particular, AT1R activation increases collagen synthesis and cell proliferation, but its overexpression activates apoptosis. CF and CMF express different levels of B1 and B2 kinin receptors, whose stimulation by their respective agonists activates common signaling transduction pathways that decrease the synthesis and secretion of collagen through nitric oxide and prostacyclin I2 secretion. Besides these classical functions, CF can also participate in the inflammatory response of cardiac repair, through the expression of receptors commonly associated to immune cells such as Toll like receptor 4, NLRP3 and interferon receptor. The activation by their respective agonists modulates the cellular functions already described and the release of cytokines and chemokines. Thus, CF and CMF act as sentinel cells responding to a plethora of stimulus, modifying their own behavior, and that of neighboring cells.