Abstract
BackgroundArterial proteoglycans are implicated in the pathogenesis of atherosclerosis by their ability to trap plasma lipoproteins in the arterial wall and by their influence on cellular migration, adhesion and proliferation. In addition, data have suggested an anti-atherogenic role for heparan sulfate proteoglycans and a pro-atherogenic role for dermatan sulfate proteoglycans. Using a non-human primate model for human diabetes, studies examined diabetes-induced changes in arterial proteoglycans that may increase susceptibility to atherosclerosis.MethodsControl (n = 7) and streptozotocin-induced diabetic (n = 8) cynomolgous monkeys were assessed for hyperglycemia by measurement of plasma glycated hemoglobin (GHb). Thoracic aortas obtained at necropsy, were extracted with 4 M guanidine HCL and proteoglycans were measured as hexuronic acid. Atherosclerosis was measured by enzymatic analysis of extracted tissue cholesterol. Glycosaminoglycan chains of arterial proteoglycans were released with papain, separated by agarose electrophoresis and analysed by scanning densitometry.ResultsTissue cholesterol was positively associated with hexuronic acid content in diabetic arteries (r = .82, p < .025) but not in control arteries. Glycosaminoglycan chain analysis demonstrated that dermatan sulfate was associated with increased tissue cholesterol in both control (r = .8, p < 0.05) and diabetic (r = .8, p < .025) arteries, whereas a negative relationship was observed between heparan sulfate and tissue cholesterol in diabetic arteries only (r = -.7, p < .05). GHb, which was significantly higher in diabetic animals (8.2 ± 0.9 vs 3.8 ± 0.2%, p < .0005) was negatively associated with heparan sulfate in diabetic arteries (r = -.7, p < .05).ConclusionsThese data implicate hyperglycemia induced modifications in arterial proteoglycans that may promote atherosclerosis.
Highlights
Arterial proteoglycans are implicated in the pathogenesis of atherosclerosis by their ability to trap plasma lipoproteins in the arterial wall and by their influence on cellular migration, adhesion and proliferation
glycated hemoglobin (GHb) was the only parameter measured that was significantly higher in the plasma of diabetic animals compared to control
A strong positive relationship was observed between thoracic aortas (TA) cholesterol and carotid artery (CA) cholesterol (r = 0.86, p < 0.0005 for both groups combined)
Summary
Arterial proteoglycans are implicated in the pathogenesis of atherosclerosis by their ability to trap plasma lipoproteins in the arterial wall and by their influence on cellular migration, adhesion and proliferation. The relative risk of CVD for diabetic versus non-diabetic individuals is 2–3 for men and 3–4 for women [4,5,6,7,8,9]. The process of entrapment and retention of LDL in arterial tissue is proposed to be mediated by arterial proteoglycans (PG) This is based on studies showing co-isolation of glycosaminoglycans (GAG), the carbohydrate moieties of PG with lipid from human atherosclerotic lesions [17,18] and immunogold labeling [19] and ultrastructural studies [20] showing LDL associated with extracellular matrix PG in rabbit arteries. In a recent study using transgenic mice expressing recombinant LDL with site specific mutations in apoB, animals with PG-binding-defective LDL developed significantly less atherosclerosis than animals expressing wild type LDL [21]
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