Effect of calcium channel blockers on proteoglycan synthesis by vascular smooth muscle cells and low density lipoprotein-proteoglycan interaction

Calcium channel blockers are known to retard atherosclerosis. In this study , we tested the hypothesis that one mechanism by which calcium channel bloc kers retard atherosclerosis is through the modulation of proteoglycan metab olism by vascular smooth muscle cells. We investigated the effect of amlodi pine and nifedipine on proteoglycan synthesis by human aortic smooth muscle cells and the ability of the newly synthesized proteoglycans to bind low d ensity lipoprotein (LDL). Confluent smooth muscle cells were incubated with [S-35]sulfate alone or [S-35]sulfate and [H-3]leucine in the presence and absence of different concentrations of amlodipine and nifedipine (0.1-20 mu g/ml) for 24 h, and newly synthesized proteoglycans were analyzed. Both aml odipine and nifedipine inhibited proteoglycan synthesis by smooth muscle ce lls in a dose-dependent manner; however, amlodipine was significantly more potent than nifedipine in this regard. In the presence of 20 mug/ml amlodip ine, media and cellular proteoglycans decreased by 56%. This was due to inh ibition of de novo proteoglycan synthesis by amlodipine. Compared with the proteoglycans synthesized by control smooth muscle cells, those synthesized by cells exposed to amlodipine were smaller and less sulfated, and contain ed fewer glycosaminoglycan chains. In addition, proteoglycans synthesized b y cells treated with amlodipine bound LDL with low affinity. These results suggest that amlodipine may protect against atherosclerosis through a prote oglycan-mediated mechanism. (C) 2001 Elsevier Science Ireland Ltd. All righ ts reserved.