Transient Receptor Potential (TRP) Channels and Cardiac Fibrosis

Abstract

Cardiac fibrosis is associated with most cardiac diseases. Fibrosis is an accumulation of excessive extracellular matrix proteins (ECM) synthesized by cardiac fibroblasts and myofibroblasts. Fibroblasts are the most prevalent cell type in the heart, comprising 75% of cardiac cells. Myofibroblasts are hardly present in healthy normal heart tissue, but appear abundantly in diseased hearts. Cardiac fibroblasts are activated by a variety of pathological stimuli, such as myocardial injury, oxidative stress, mechanical stretch, and elevated autocrine-paracrine mediators, thereby undergoing proliferation, differentiation to myofibroblasts, and production of various cytokines and ECM proteins. A number of signaling pathways and bioactive molecules are involved and work in concert to activate fibroblasts and myofibroblasts in the fibrogenesis cascade. Fibroblasts and myofibroblasts are not only principal ECM producers, but also play a central role in fibrogenesis and myocardial remodeling in fibrotic heart disease. Thus, understanding the biological processes of cardiac fibroblasts will provide novel insights into the underlying mechanisms of fibrosis and provide potential targets for developing anti-fibrotic drugs. Recent studies demonstrate that Ca2+ signal is essential for fibroblast proliferation, differentiation, and ECM-protein production. This review focuses on the recent advances in understanding molecular mechanisms of Ca2+ signaling in cardiac fibrogenesis, and potential role of Ca2+-permeable channels, in particular, the transient potential (TRP) channels in fibrotic heart disease. TRP channels are highly expressed in cardiac fibroblasts. TRPM7 has been shown to be essential in TGFβ1 mediated fibrogenesis, and TRPC3 has been demonstrated to play an essential role in regulating fibroblast function. Thus, the Ca2+-permeable TRP channels may serve as potential novel targets for developing anti-fibrotic drugs.

Transient Receptor Potential Melastatin 7 (TRPM7) Contributes to H2O2-Induced Cardiac Fibrosis via Mediating Ca2+ Influx and Extracellular Signal–Regulated Kinase 1/2 (ERK1/2) Activation in Cardiac Fibroblasts

“…Extensive evidence has shown that there is a welldocumented association of Ca 2+ and cardiac fibrosis (6,27). Intervention and modulation of Ca 2+ channels and Ca…”

“…Although the expression of some TRP channels can be detected by using RT-PCR and appears to be associated with cardiac fibrosis, many of them cannot be detected by using electrophysiological recordings (6,30). Du and colleagues have found that silencing TRPM7 greatly diminishes the endogenous TRPM7 currents and Ca 2+ influx, which impairs the sensitivity of human atrial fibroblasts to TGF-b1-induced proliferation and differentiation.…”

“…Being the predominant cell type in the heart, up to 65% of total cell numbers (4), cardiac fibroblasts have been demonstrated to contribute greatly to cardiac fibrosis-related diseases (5). Various deleterious stimuli can promote cardiac fibroblasts to proliferate, migrate, and undergo functional changes, including differentiation into myofibroblasts, production of ECM proteins, and release of cytokines and growth factors, which in turn further stimulates cardiac fibroblasts, leading to persistent fibrosis (6). Irrespective of the initial stimuli, cardiac fibroblasts are the determinant contributor in cardiac fibrosis.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Transient Receptor Potential Channels and Cardiac Fibrosis. Cardiac fibrosis is not a distinct entity; rather, it is a common pathologic pathway for various diseases (e.g., AMI and chronic ischemic heart disease, inflammatory and hypertrophic cardiomyopathies, and aging-associated heart disease) that damages the myocardium (reviewed in Yue et al, 2013). The damaged myocardium is then replaced by connective tissue synthesized by fibroblasts and myofibroblasts.…”

“…By contrast, myofibroblasts are rare in the healthy heart but become enriched during disease. In response to pathogenic stimuli (e.g., myocardial injury, oxidative stress, and/or mechanical stretch), fibroblasts get activated and a subset differentiates into myofibroblasts (see Yue et al, 2013). In turn, activated fibroblasts and myofibroblasts excessively synthesize and deposit extracellular matrix proteins.…”