TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation.
BACKGROUND
Cardiac fibrosis contributes to pathogenesis of atrial fibrillation (AF), which is the most commonly sustained arrhythmia and a major cause of morbidity and mortality. Although it has been suggested that Ca(2+) signals are involved in fibrosis promotion, the molecular basis of Ca(2+) signaling mechanisms and how Ca(2+) signals contribute to fibrogenesis remain unknown.


OBJECTIVE
To determine the molecular mechanisms of Ca(2+)-permeable channel(s) in human atrial fibroblasts, and to investigate how Ca(2+) signals contribute to fibrogenesis in human AF.


RESULTS
We demonstrate that the transient receptor potential (TRP) melastatin related 7 (TRPM7) is the molecular basis of the major Ca(2+)-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 largely eliminates TRPM7 current and Ca(2+) influx in atrial fibroblasts. More importantly, atrial fibroblasts from AF patients show a striking upregulation of both TRPM7 currents and Ca(2+) influx and are more prone to myofibroblast differentiation, presumably attributable to the enhanced expression of TRPM7. TRPM7 small hairpin RNA markedly reduced basal AF fibroblast differentiation. Transforming growth factor (TGF)-beta1, the major stimulator of atrial fibrosis, requires TRPM7-mediated Ca(2+) signal for its effect on fibroblast proliferation and differentiation. Furthermore, TGF-beta1-induced differentiation of cultured human atrial fibroblasts is well correlated with an increase of TRPM7 expression induced by TGF-beta1.


CONCLUSIONS
Our results establish that TRPM7 is the major Ca(2+)-permeable channel in human atrial fibroblasts and likely plays an essential role in TGF-beta1-elicited fibrogenesis in human AF.
Du
Jianyang
J
Department of Cell Biology/Cardiology, ARB EG024, MC-3946, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030, USA.
Xie
Jia
J
Zhang
Zheng
Z
Tsujikawa
Hiroto
H
Fusco
Daniel
D
Silverman
David
D
Liang
Bruce
B
Yue
Lixia
L
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling; D002454:Cell Differentiation; D002463:Cell Membrane Permeability; D049109:Cell Proliferation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D034622:RNA Interference; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
D050053:TRPM Cation Channels; D053773:Transforming Growth Factor beta1; C421903:Trpm7 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human