Statin-exposed vascular smooth muscle cells secrete proteoglycans with decreased binding affinity for LDL.
Retention of LDL in the artery intima is mediated by extracellular matrix proteoglycans and plays an important role in the initiation of atherosclerosis. Compared with quiescent cells, proliferating smooth muscle cells secrete proteoglycans with elongated glycosaminoglycan side chains, which have an increased binding affinity to LDL. Because 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) decrease smooth muscle cell proliferation, we hypothesized that statin exposure would decrease both the size and LDL binding affinity of vascular proteoglycans. Monkey aortic smooth muscle cells grown in culture were exposed to simvastatin (10 and 100 microM) and cerivastatin (0.1 and 1 microM), and newly secreted proteoglycans were quantified and characterized. Both simvastatin and cerivastatin caused a concentration-dependent reduction in cell growth and reduced 35SO4 incorporation into secreted proteoglycans, on both an absolute and a per cell basis. Interestingly, statin exposure increased the apparent molecular weight and hydrodynamic size of secreted proteoglycans. However, proteoglycans secreted from statin-exposed cells demonstrated a reduction in binding affinity to LDL. Thus, statins may induce atheroprotective changes in vascular proteoglycans and lower LDL retention in the vessel wall. These findings suggest a mechanism whereby statins may benefit atherosclerosis in a manner unrelated to serum LDL lowering.
Meyers
C Daniel
CD
Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, School of Medicine, Box 356426, University of Washington, Seattle, WA 98195-6426, USA.
Tannock
Lisa R
LR
Wight
Thomas N
TN
Chait
Alan
A
D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D004224:Diterpenes / Q000378:metabolism; D005944:Glucosamine / Q000378:metabolism; D000882:Haplorhini; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism*
D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D011509:Proteoglycans; D008715:Methionine; C017338:geranylgeraniol; D005944:Glucosamine; D008798:Mevalonic Acid