Alam R, Kataoka S, Alam S, Yatsu F
University of Texas Medical School at Houston, 77030, USA.
Atherosclerosis. 1996 Oct 25;126(2):207-19. doi: 10.1016/0021-9150(96)05908-4.
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.
血管平滑肌细胞的增殖被认为是动脉粥样硬化形成的一个致病因素。钙通道阻滞剂已被证明可延缓动脉粥样硬化的进展。为了阐明这些药物介导此类作用的机制，我们研究了一种新型钙拮抗剂克仑硫䓬对血管平滑肌细胞体外增殖的影响。克仑硫䓬可显著抑制血小板衍生生长因子（PDGF）诱导的这些细胞的增殖。提示蛋白激酶C（PKC）可能参与了这种细胞反应。克仑硫䓬似乎可抑制佛波酯和PDGF-BB诱导的PKC易位以及血管平滑肌细胞中PKC的80 kDa蛋白底物的磷酸化。此外，用克仑硫䓬处理会导致特异性佛波酯结合位点的数量显著减少。对蛋白激酶C的膜结合同工酶的分析表明，这种抑制作用对δ酶具有特异性。克仑硫䓬对动脉胆固醇酯水解没有显著影响。我们的结果表明，克仑硫䓬可能通过调节胞质PKC并阻止其膜易位和激活来抑制细胞增殖。
