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

de Dios, Stephanie T., Frontanilla, Karen V., Nigro, Julie, Ballinger, Mandy L., Ivey, Melanie E., Cawson, Elizabeth A. and Little, Peter J. (2007) Regulation of the atherogenic properties of vascular smooth muscle proteoglycans by oral anti-hyperglycemic agents. Journal of Diabetes and its Complications, 21 2: 108-117. doi:10.1016/j.jdiacomp.2006.03.003


Author de Dios, Stephanie T.
Frontanilla, Karen V.
Nigro, Julie
Ballinger, Mandy L.
Ivey, Melanie E.
Cawson, Elizabeth A.
Little, Peter J.
Title Regulation of the atherogenic properties of vascular smooth muscle proteoglycans by oral anti-hyperglycemic agents
Journal name Journal of Diabetes and its Complications   Check publisher's open access policy
ISSN 1056-8727
1873-460X
Publication date 2007-03
Sub-type Article (original research)
DOI 10.1016/j.jdiacomp.2006.03.003
Open Access Status Not yet assessed
Volume 21
Issue 2
Start page 108
End page 117
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Formatted 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 [35S]-SO4 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 [35S]-SO4 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-β1 (TGF-β1), caused by an inhibition of proteoglycan core protein synthesis secondary to a reduction in total protein synthesis. However, neither metformin nor phenformin (30-300 μmol/l) had any effect on the electrophoretic mobility of proteoglycans. The TZDs-troglitazone (TRO), rosiglitazone (ROS), and pioglitazone (PIO) (10, 30, and 30 μmol/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.
Keyword Atherosclerosis
Oral hypoglycemic agents
Proteoglycans
Type 2 diabetes mellitus
Vascular smooth muscle cells
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Pharmacy Publications
 
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