L-calcium channel blockade induced by diltiazem inhibits proliferation, migration and F-actin membrane rearrangements in human vascular smooth muscle cells stimulated with insulin and IGF-1.
During the atheroma plaque formation, smooth muscle cells (SMC) have to change their differentiated phenotype in order to proliferate, migrate and synthesize collagen. These phenotypic changes are stimulated by insulin and IGF-1, and we have studied the effect of L-type calcium channel blockade produced by diltiazem on such changes. Mitotic activity was measured using bromodeoxyuridine DNA incorporation, the migration capability as chemotaxis index in a Boyden chamber, and cytoskeleton changes related to SMC movement in immunofluorescence studies. Diltiazem (10(-7)-10(-6) M) reduced insulin-induced mitotic activity in cultured human vascular SMC more effectively than in IGF-1-induced mitotic activity, but at 10(-5) M, the inhibitory effects were similar. Diltiazem also showed a clear inhibition of migration ability, both under basal conditions (p < 0.05) and after addition of insulin (p = 0.0001) and IGF-1 (p < 0.0001). Finally, diltiazem inhibited membrane ruffling induced both by insulin and IGF-1 in a similar manner, and similar results were obtained with SMC from rat aorta. We conclude that substances blocking the L-type calcium channels such as diltiazem, could inhibit those processes which in vivo lead SMC to form the atheroma plaque.
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D003599:Cytoskeleton / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007328:Insulin / Q000494:pharmacology* / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D051381:Rats
D000199:Actins; D002121:Calcium Channel Blockers; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D004110:Diltiazem