A TRP to cardiac fibroblast differentiation

Abstract

The differentiation of cardiac fibroblasts to myofibroblasts is one of the key events during cardiac remodeling, however, the molecular mechanism underlying this process is not well known. Calcium signaling plays an important role in the regulation of cardiac fibroblast function, but its role in the differentiation of fibroblasts is undefined. Recently four Transient Receptor Potential (TRP) channels TRPM7, TRPC3, TRPC6 and TRPV4 were shown to be crucial for the differentiation of cardiac fibroblasts to myofibroblasts. This addendum sums up the roles described for these four TRP channels in cardiac fibroblast differentiation, and discusses the possible molecular mechanisms underlying this process and its relevance for cardiac remodeling in disease.

Keywords: ECM stiffness; Rho/ROCK; TRPV4; cardiac fibroblast; differentiation; integrin; mechanical signaling; myofibroblast.

Figure 1. A proposed model showing the mechanism(s) by which TRP channels regulate fibroblast differentiation to myofibroblasts during cardiac remodeling (adapted from ref. 16). The soluble profibrotic factors such as TGFβ^- and Ang II induce expression of TRP channels via p38/SRF or NFAT/miR-26, which in turn activate signaling cascades involved in fibroblast proliferation (TRPC3/ERK1/2¹⁸) and α-SMA expression (TRPC6/CnA/NFAT¹⁶). These chemical signals then integrate with mechanical signals (ECM stiffness/integrin/TRPV4/Rho-ROCK¹⁵) leading to incorporation α-SMA into actin stress fibers. The increased cell contraction and tensional forces may activate additional integrins (red arrows) leading to the increased ECM stiffness and activation of latent TGFβ.TGFβ = transforming growth factor β; Ang II = angiotensin II; can, calcineurin; SRF, serum responsive factor; NFAT, Nuclear factor of activated T-cells; miR-26, microRNA26; α-SMA, α-smooth muscle actin; ECM, extracellular matrix; ROCK, Rho associated protein kinase.