The effects of calcium channel blockade on proliferation and differentiation of cardiac progenitor cells |
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Institution: | 1. Bone and Joint Disease Research Center, Department of Orthopedic Surgery, Chamran Hospital, Shiraz University of Medical Sciences, Shiraz, Iran;2. Department of Pathology, Chamran Hospital, Shiraz University of Medical Sciences, Shiraz, Iran;3. McGill University, Montreal, Quebec, Canada |
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Abstract: | Cardiogenesis depends on a tightly regulated balance between proliferation and differentiation of cardiac progenitor cells (CPCs) and their cardiomyocyte descendants. While exposure of early mouse embryos to Ca2+ channel antagonists has been associated with abnormal cardiac morphogenesis, less is known about the consequences of Ca2+ channel blockade on proliferation and differentiation of CPCs at the cellular level. Here we showed that at embryonic day (E) 11.5, the murine ventricles express several L-type and T-type Ca2+ channel isoforms, and that the dihydropyridine Ca2+ channel antagonist, nifedipine, blunts isoproterenol induced increases in intracellular Ca2+. Nifedipine mediated Ca2+ channel blockade was associated with a reduction in cell cycle activity of E11.5 CPCs and impaired assembly of the cardiomyocyte contractile apparatus. Furthermore, in cell transplantation experiments, systemic administration of nifedipine to adult mice receiving transplanted E11.5 ventricular cells (containing CPCs and cardiomyocytes) was associated with smaller graft sizes compared to vehicle treated control animals. These data suggest that intracellular Ca2+ is a critical regulator of the balance between CPC proliferation and differentiation and demonstrate that interactions between pharmacological drugs and transplanted cells could have a significant impact on the effectiveness of cell based therapies for myocardial repair. |
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Keywords: | Embryonic heart Cardiac progenitor cells Cardiomyocytes Lineage tracking Transgenic and knockin mice Cell proliferation and differentiation Gene expression analysis Calcium channel blocker Calcium imaging L and T type calcium channels Myofibrillogenesis Nifedipine Isoproterenol Cell transplantation Donor cells and drug interactions |
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