Oleate, not ligands of the receptor for advanced glycation end-products, promotes proliferation of human arterial smooth muscle cells.
OBJECTIVE
Diabetes accelerates cardiovascular disease caused by atherosclerosis. Accordingly, diabetes accelerates atherosclerotic lesion progression and increases arterial smooth muscle cell proliferation. We hypothesized that diabetes can exert growth-promoting effects on smooth muscle cells via increased advanced glycation end-products or by dyslipidaemia.


METHODS
Primary human arterial smooth muscle cells were stimulated with advanced glycation end-products, other ligands of the receptor for advanced glycation end-products or fatty acids common in triglycerides. Cell proliferation was measured as DNA synthesis, cell cycle distribution and cell number. Effects of oleate on cellular phospholipids, diacylglycerol, triglycerides and cholesterol esters were analyzed by thin-layer chromatography, and oleate accumulation into diacylglycerol was confirmed by gas chromatography.


RESULTS
Human arterial smooth muscle cells express the receptor for advanced glycation end-products, but its ligands N(epsilon)-(carboxymethyl)lysine-modified proteins, methylglyoxal-modified proteins, S100B polypeptide and amyloid-beta (1-40) peptide, exert no mitogenic action. Instead, oleate, one of the most common fatty acids in triglycerides, enhances platelet-derived growth factor-BB-mediated proliferation and oleate-containing 1,2-diacylglycerol formation in smooth muscle cells. This mitogenic effect of oleate depends on phospholipase D activity and is associated with an increased formation of oleate-enriched 1,2-diacylglycerol.


CONCLUSIONS
Oleate, not ligands of the receptor for advanced glycation end-products, acts as an enhancer of human smooth muscle cell proliferation. Thus, lipid abnormalities, rather than hyperglycaemia, could be a major factor promoting proliferation of smooth muscle cells in atherosclerotic lesions.
Department of Pathology, University of Washington School of Medicine, Box 357470, Seattle, WA 98195-7470, USA.
C B
CB
Renard
B
B
Askari
L A
LA
Suzuki
F
F
Kramer
K E
KE
Bornfeldt
D001011:Aorta; D001161:Arteriosclerosis / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D007231:Infant, Newborn; D008024:Ligands; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D019301:Oleic Acid / Q000494:pharmacology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology*
D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019301:Oleic Acid