Atheroprotective remodelling of vascular dermatan sulphate proteoglycans in response to hypercholesterolaemia in a rat model

Factors that determine early atherosclerotic lesions are unknown, but the vascular extracellular matrix (ECM) appears to be involved. Two hypotheses, which directly or indirectly reflect ECM involvement, have been proposed to explain the early molecular events of this pathology. The first hypothesis is the response-to-retention hypothesis, which emphasizes that the interaction between ECM molecules, particularly proteoglycans (PGs) and lipoproteins, is the key event in early atherogenesis (Williams & Tabas 1995; Camejo et al. 1998; Skalen et al. 2002). The second hypothesis is the chronic inflammation hypothesis (Ross 1999; Tedgui & Mallat 2006), in which the binding of cytokines and growth factors to ECM PGs may increase the residence time of these molecules in the extracellular environment and modulate their functional activity dynamically (Camejo et al. 1995; Young & Murphy-Ullrich 2004; Groeneveld et al. 2005). Consequently, the expression and distribution of arterial PGs are significantly modulated during atherosclerosis and ageing (Tovar et al. 1998). For instance, human atherosclerosis-prone arteries express PGs, such as biglycan and decorin, in the outer layer of the intima of prelesional areas preceding lipid deposition (Nakashima et al. 2007). Besides, GAG chains attached to the protein core of PGs undergo specific structural modifications during the development of the disease. Elongated GAG chains have been reported in human early atherosclerotic lesions (Theocharis et al. 2002; Little et al. 2007). For instance, hyperelongated chondroitin sulphate (CS) chains of biglycan may be the key factor for atherosclerosis, because they enhance the low-density lipoprotein (LDL) binding affinity (Anggraeni et al. 2011). As it is known, hypercholesterolaemia is a dominant risk factor for atherosclerosis. Cholesterol feeding has been used to increase serum cholesterol levels and then to assess hypercholesterolaemia-related metabolic disturbances in different animal models (Deepa & Varalakshmi 2005; Hachani et al. 2011; Raman et al. 2011). In contrast to that observed in humans, in rats, hypercholesterolaemia alone is unable to induce intimal thickening and atheroma plaque development, mainly as a consequence of the lack of cholesteryl ester transfer protein (CETP) (Hogarth et al. 2003; Hachani et al. 2010). The aim of this study was to analyse quantitative and structural modifications of PGs in aortas isolated from rats upon treatment with a high-cholesterol diet, to understand whether vascular wall remodelling may protect against the atheroma lesions.