Calcium channel regulation in vascular smooth muscle cells: synergistic effects of statins and calcium channel blockers.
In the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) we have reported a positive interaction between atorvastatin and amlodipine-based antihypertensive strategy in terms of the prevention of coronary events. In cellular and molecular studies on human vascular smooth muscle cells (VSMC) we have reported that transformation from a differentiated to a synthetic or dedifferentiated phenotype is associated with loss of function of L-type calcium channels and hence loss of potential responsiveness to calcium channel blockers (CCB). Statins directly inhibit cell cycle progression and dedifferentiation of VSMC due to their ability to inhibit the synthesis of isoprenoid cholesterol intermediates. We hypothesize that statins promote a more differentiated VSMC phenotype that results in upregulation of L-type calcium channels and restoration of a CCB-sensitive calcium influx pathway in VSMC, favourably affecting the balance that exists between VSMC proliferation, apoptosis and matrix metalloproteinase production with an associated increase in stability of atheromatous plaques.
Clunn
Gerard F
GF
Imperial College London, UK. p.sever@imperial.ac.uk
Sever
Peter S
PS
Hughes
Alun D
AD
D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D015220:Calcium Channels / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors