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 blockers retard atherosclerosis is through the modulation of proteoglycan metabolism by vascular smooth muscle cells. We investigated the effect of amlodipine and nifedipine on proteoglycan synthesis by human aortic smooth muscle cells and the ability of the newly synthesized proteoglycans to bind low density lipoprotein (LDL). Confluent smooth muscle cells were incubated with [(35)S]sulfate alone or [(35)S]sulfate and [(3)H]leucine in the presence and absence of different concentrations of amlodipine and nifedipine (0.1--20 microg/ml) for 24 h, and newly synthesized proteoglycans were analyzed. Both amlodipine and nifedipine inhibited proteoglycan synthesis by smooth muscle cells in a dose-dependent manner; however, amlodipine was significantly more potent than nifedipine in this regard. In the presence of 20 microg/ml amlodipine, media and cellular proteoglycans decreased by 56%. This was due to inhibition 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 contained fewer glycosaminoglycan chains. In addition, proteoglycans synthesized by cells treated with amlodipine bound LDL with low affinity. These results suggest that amlodipine may protect against atherosclerosis through a proteoglycan-mediated mechanism.
Vijayagopal
P
P
Section of Cardiology, Department of Medicine, Louisiana State University Health Sciences Center, 1542 Tulane Avenue, New Orleans, LA 70112, USA. pvijay@lsuhsc.edu
Subramaniam
P
P
D017311:Amlodipine / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology*; D011509:Proteoglycans / Q000096:biosynthesis / Q000378:metabolism*
D002121:Calcium Channel Blockers; D008077:Lipoproteins, LDL; D011509:Proteoglycans; D017311:Amlodipine; D009543:Nifedipine