Abstract 1530: TRPM7-mediated Ca2+ Signal And Cardiac Fibroblast Differentiation In Atrial Fibrillation Patients
Background Cardiac fibrosis is associated with a variety of heart diseases including atrial fibrillation (AF). Cardiac fibroblasts play an important role in cardiac fibrogenesis. Upon stimulation, fibroblasts differentiate to myofibroblasts, which contribute significantly to fibrosis formation. We have shown that TRPM7 is a major Ca2+ entry channel in the cardiac fibroblasts. Here, we investigated the potential role of TRPM7 in fibroblast differentiation.
Methods With informed consent, right atrial biopsies were obtained from patients undergoing cardiac surgery. Six patients were with sinus rhythms (n=6: 5M, 1F; mean age 66±8 yrs), and five patients with AF (n=5: 3M, 2F; mean age 68±9 yrs). Fibroblasts were dissociated from the biopsy samples from either control patients (with sinus rhythm) or AF patients. The isolated cells were cultured for inducing transformation by TGF-β1. After differentiation, myofibroblasts were evaluated by immunostaining with Anti-SMA. TRPM7 specific siRNA was used to knock-down TRPM7 expression when it was necessary.
Results We found that TRPM7 current amplitude in AF patients was three-fold bigger than that in control patients. Ca2+ influx mediated by TRPM7 was also remarkably bigger in AF patients than that in control patients. After culture, some fibroblasts differentiated into myofibroblasts without any stimulation. This basal level of differentiation was much higher in cells from AF patients than those from control patients. Upon stimulation by 10 ng/ml TGF-β1, the majority of fibroblast transformed to myofibroblasts. And fibroblasts from AF patients were more vulnerable to TGF-β1 stimulation. Interestingly, we found that after the fibroblasts were treated by TRPM7 siRNA which can decrease 76% TRPM7 current, the differentiation at both basal level and stimulated by TGF- β1 was significantly decreased in both control and AF patients.
Conclusions Our results indicate that TRPM7 is involved in cardiac fibroblast differentiation. This study and our other study provide a novel molecule (TRPM7) as well as a novel mechanism for cardiac fibrogenesis: TRPM7-mediated Ca2+ signal is important in cardiac fibroblast differentiation, which largely contributes to cardiac fibrogenesis and associated heart diseases.