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Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis

Authors Peter J Little, Mandy L. Ballinger, Narin Osman

Published 15 March 2007 Volume 2007:3(1) Pages 117—124

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Peter J Little1, 2, 3, Mandy L. Ballinger1, Narin Osman1,3

1Cell Biology of Diabetes Laboratory, Baker Heart Research Institute, Melbourne, Australia; Monash University, Departments of 2Medicine and 3Immunology, Central and Eastern Clinical School, Alfred Hospital, Melbourne, Australia

Abstract: Atherosclerosis is the underlying pathology of most cardiovascular disease and it represents the major cause of premature death in modern societies. Current therapies target risk factors being hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycemia when diabetes is present however the maximum efficacy of these strategies is often 30% or less. Areas of vascular biology that may lead to the development of a complementary vascular wall directed therapy are: inflammation, oxidation, endothelial dysfunction, diabetes-specific factors —hyperglycemia and advanced glycation endproducts and lipid retention by vascular matrix specifically proteoglycans. The major structural features of proteoglycans that determine low-density lipoprotein (LDL) binding are the length and sulfation pattern on the glycosaminoglycan (GAG) chains. Emerging data discussed in this review indicates that these structural properties are subject to considerable regulation by vasoactive substances possibly using novel signaling pathways. For example, GAG elongation stimulated by platelet-derived growth factor is not blocked by the receptor tyrosine kinase antagonist, genistein suggesting that there may be a previously unknown signaling pathway involved in this response. Thus, modifying proteoglycan synthesis and structure may represent a prime target to prevent LDL binding and entrapment in the vessel wall and thus prevent the development and progression of atherosclerosis.

Keywords: proteoglycans, signaling, lipoproteins, atherosclerosis

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