Regulation of the atherogenic properties of vascular smooth muscle proteoglycans by oral anti-hyperglycemic agents

Stephanie de Dios, Karen V Frontanilla, Julie Nigro, Mandy L Ballinger, Melanie Elise Ivey, Elizabeth A Cawson, Peter J Little

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20 Citations (Scopus)

Abstract

The present study aimed to investigate the actions of several classes of oral hypoglycemic agents [e.g., sulfonylureas (SUs), biguanides (BGs) and thiazolidinediones (TZDs)] in an in vitro model of lipid binding based on the response to retention hypothesis of atherogenesis. The incorporation of [(35)S]-SO(4) into proteoglycans synthesized by human vascular smooth muscle cells (VSMCs) was assessed by cetylpyridinium chloride (CPC) precipitation method, proteoglycan electrophoretic mobility was evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and binding to low-density lipoprotein (LDL) was assessed by gel mobility shift assay (GMSA). The SUs evaluated showed no effect on [(35)S]-SO(4) incorporation into proteoglycans. Only one BG, phenformin, caused a concentration-related inhibition of proteoglycan synthesis under basal conditions and in the presence of transforming growth factor-beta1 (TGF-beta1), caused by an inhibition of proteoglycan core protein synthesis secondary to a reduction in total protein synthesis. However, neither metformin nor phenformin (30-300 micromol/l) had any effect on the electrophoretic mobility of proteoglycans. The TZDs--troglitazone (TRO), rosiglitazone (ROS), and pioglitazone (PIO) (10, 30, and 30 micromol/l, respectively)--inhibited proteoglycan biosynthesis and stimulated total proteoglycan core protein synthesis, while TRO alone inhibited overall protein synthesis. All three TZDs moderately reduced the electrophoretic mobility of synthesized proteoglycans assessed by SDS-PAGE, reduced the sizes of cleaved glycosaminoglycan (GAG) chains assessed by size exclusion chromatography, and significantly reduced binding to LDL. The data indicate that TZDs show anti-atherogenic actions through the modification of proteoglycan structure, leading to a possible reduction in lipid retention in the vessel wall.
Original languageEnglish
Pages (from-to)108 - 117
Number of pages10
JournalJournal of Diabetes and its Complications
Volume21
Issue number2
Publication statusPublished - 2007

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