Cell cycle dependent regulation of intracellular calcium concentration in vascular smooth muscle cells: a potential target for drug therapy.
Intracellular Ca2+ transients have been shown to control several transition points within the eukaryotic cell cycle. We focus here on the G1-to-S phase transition triggered by an increase in the intracellular Ca2+ concentration ([Ca2+](i)) in rodent vascular smooth muscle cells (VSMC) and its potential targeting for the treatment of vaso-occlusive processes such as atherosclerosis, hypertension and post-angioplasty restenosis. The transcription factor c-Myb generates a G1/S transition-specific Ca2+ transient via its regulation of a high affinity Ca2+ efflux pump, the plasma membrane Ca2+ ATPase-1 (PMCA1). The cell cycle-associated repression of PMCA1 is mediated by two c-Myb binding sites in the PMCA1 promoter. As c-Myb levels increase in late G1 phase of proliferating VSMC, transcription from the PMCA1 promoter is reduced, expression of the PMCA1 gene falls, and the resultant reduced rate of Ca2+ efflux underlies a G1/S-associated increase in [Ca2+](i). Blocking either the upregulation of c-Myb levels, or the down regulation in expression of the efflux pump, leads to significant reductions in S phase entry and proliferation of VSMC. A search for functional c-Myb sites within the promoters of other Ca2+ transporters has been undertaken in order to extend the molecular framework of the G1/S-specific Ca2+ signal mediated by the c-Myb transcription factor. Animal studies with c-myb antisense oligodeoxynucleotides and an anti-c-myb ribozyme as well as in vitro results with dominant negative c-Myb mutants and a doxycycline-inducible c-Myb neutralizing antibody point to the potential of c-Myb-targeted gene therapy for treating pathologic VSMC proliferation and highlight the need for clinical trials in this field.
Afroze
T
T
Department of Medicine, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
Husain
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D002118:Calcium