Document Type

Article

Disciplines

Cardiology | Medicine and Health Sciences

Abstract

Rationale—Cardiac fibrosis contributes to pathogenesis of atrial fibrillation (AF), which is the most sustained arrhythmia and a major cause of morbidity and mortality. Although it has been suggested that Ca2+ signals are involved in fibrosis promotion, the molecular basis of Ca2+ signaling mechanisms and how Ca2+ signals contribute to fibrogenesis remain unknown.
Objective—To determine the molecular mechanisms of Ca2+-permeable channel(s) in human atrial fibroblasts, and to investigate how Ca2+ signals contribute to fibrogenesis in human AF.
Methods and Results—We demonstrate that the transient receptor potential melastatin related 7 (TRPM7) is the molecular basis of the major Ca2+-permeable channel in human atrial fibroblasts. Endogenous TRPM7 currents in atrial fibroblasts resemble the biophysical and pharmacological properties of heterologous expressed TRPM7. Knocking down TRPM7 by small hairpin RNA (shRNA) largely eliminates TRPM7 current and Ca2+ influx in atrial fibroblasts. More importantly, atrial fibroblasts from AF patients show a striking upregulation of both TRPM7 currents and Ca2+ influx and are more prone to myofibroblast differentiation, presumably due to the enhanced expression of TRPM7. TRPM7-shRNA markedly reduced basal AF fibroblast differentiation. Transforming growth factor β1 (TGF-β1), the major stimulator of atrial fibrosis, requires TRPM7-mediated Ca2+ signal for its effect on fibroblast proliferation and differentiation. Furthermore, TGF-β1 induced differentiation of cultured human atrial fibroblasts is well correlated with an increase of TRPM7 expression induced by TGF-β1.
Conclusions—Our results establish that TRPM7 is the major Ca2+-permeable channel in human atrial fibroblasts, and likely plays an essential role in TGF-β1-elicited fibrogenesis in human AF.

Comments

Circ Res. Author manuscript; available in PMC 2011 March 19. Published in final edited form as: Circ Res. 2010 March 19; 106(5): 992–1003. Published online 2010 January 14. doi: 10.1161/CIRCRESAHA.109.206771.

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