title: The effects of calcium channel blockade on proliferation and differentiation of cardiac progenitor cells.
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 Ca(2+) channel antagonists has been associated with abnormal cardiac morphogenesis, less is known about the consequences of Ca(2+) 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 Ca(2+) channel isoforms, and that the dihydropyridine Ca(2+) channel antagonist, nifedipine, blunts isoproterenol induced increases in intracellular Ca(2+). Nifedipine mediated Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Hotchkiss
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Tiam
authors.initials: T
authors.lastname: Feridooni
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Feixiong
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address: kpasumar@dal.ca.
authors.forename: Kishore B S
authors.initials: KB
authors.lastname: Pasumarthi
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000737:chemistry / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056744:Cyclin B1 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D064326:MEF2 Transcription Factors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D056744:Cyclin B1; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D009543:Nifedipine; D007545:Isoproterenol; D002118:Calcium
keywords: Calcium channel blocker; Calcium imaging; Cardiac progenitor cells; Cardiomyocytes; Cell proliferation and differentiation; Cell transplantation; Donor cells and drug interactions; Embryonic heart; Gene expression analysis; Isoproterenol; L and T type calcium channels; Lineage tracking; Myofibrillogenesis; Nifedipine; Transgenic and knockin mice