Inhibition of vascular smooth muscle cell proliferation by the calcium antagonist clentiazem: role of protein kinase C.
The proliferation of vascular smooth muscle cells has been implicated as a causative factor in atherogenesis. Calcium channel blockers have been shown to retard the progression of atherosclerosis. To elucidate the mechanism by which these drugs mediate such actions, we studied the effects of a new calcium antagonist, clentiazem, on the in vitro proliferation of vascular smooth muscle cells. PDGF-induced prolifertion of these cells is markedly inhibited by clentiazem. The probable involvement of protein kinase C (PKC) in this cellular response is suggested. Clentiazem appear to cause inhibition of PKC translocation that is induced by phorbol esters and PDGF-BB and the phosphorylation of the 80 kDa protein substrate of PKC in vascular smooth muscle cells. Moreover, treatment with clentiazem leads to a marked decrease in the number of specific phorbol ester binding sites. Analysis of the membrane bound isoenzymes of protein kinase C revealed that the inhibition was specific to delta enzymes. Arterial cholesterol ester hydrolysis is not significantly altered by clentiazem. Our results suggest that clentiazem may inhibit cell proliferation by regulating cytosolic PKC and preventing its membrane translocation and activation.
University of Texas Medical School at Houston, 77030, USA.
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Alam
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Kataoka
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Alam
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Yatsu
D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002788:Cholesterol Esters / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats
D002121:Calcium Channel Blockers; D002788:Cholesterol Esters; D007527:Isoenzymes; D015240:Phorbol 12,13-Dibutyrate; C056595:clentiazem; D000249:Adenosine Monophosphate; D004247:DNA; D011493:Protein Kinase C; D004110:Diltiazem