title: Atheroprotective remodelling of vascular dermatan sulphate proteoglycans in response to hypercholesterolaemia in a rat model.
abstract: Proteoglycan accumulation within the arterial intima has been implicated in atherosclerosis progression in humans. Nevertheless, hypercholesterolaemia is unable to induce intimal thickening and atheroma plaque development in rats. The study was performed to analyse proteoglycans modifications in rats fed with a high-cholesterol diet to understand whether vascular wall remodelling protects against lesions. Sections obtained from rat aortas showed normal features, in intimal-to-media ratio and lipid accumulation. However, focal endothelial hyperplasia and neo-intima rearrangement were observed in high-cholesterol animals. Besides, hypercholesterolaemia induced an inflammatory microenviroment. We determined the expression of different proteoglycans from aortic cells by Western blot and observed a diminished production of decorin and biglycan in high-cholesterol animals compared with control (P < 0.01 and P < 0.05, respectively). Versican was increased in high-cholesterol animals (P < 0.05), whereas perlecan production showed no differences. No modification of the total content of glycosaminoglycans (GAGs) was found between the two experimental groups. In contrast, the chondroitin sulphate/dermatan sulphate ratio was increased in the high-cholesterol group as compared to the control (0.56 and 0.34, respectively). Structural alterations in the disaccharide composition of galactosaminoglycans were also detected by HPLC, as the ratio of 6-sulphate to 4-sulphate disaccharides was increased in high-cholesterol animals (P < 0.05). Our results suggest that attenuation of decorin and biglycan expression might be an effective strategy to inhibit the first step in atherogenesis, although specific GAG structural modification associated with the development of vascular disease took place. Results emphasize the potential application of therapies based on vascular matrix remodelling to treat atherosclerosis.
authors.affiliation: Cátedra de Biología Celular y Molecular, Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Roxana
authors.initials: R
authors.lastname: Oberkersch
authors.forename: Francesca
authors.initials: F
authors.lastname: Maccari
authors.forename: Alicia I
authors.initials: AI
authors.lastname: Bravo
authors.forename: Nicola
authors.initials: N
authors.lastname: Volpi
authors.forename: Silvina
authors.initials: S
authors.lastname: Gazzaniga
authors.forename: Graciela C
authors.initials: GC
authors.lastname: Calabrese
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D050197:Atherosclerosis / Q000503:physiopathology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D003871:Dermatan Sulfate / Q000737:chemistry / Q000378:metabolism*; D004036:Diet, Atherogenic / Q000009:adverse effects; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D006025:Glycosaminoglycans / Q000737:chemistry; D006041:Goats; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism / Q000503:physiopathology*; D008055:Lipids / Q000097:blood; D008297:Male; D058226:Plaque, Atherosclerotic / Q000517:prevention & control*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D006025:Glycosaminoglycans; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; C032649:dermatan sulfate proteoglycan; D003871:Dermatan Sulfate; D002784:Cholesterol
keywords: aortic cells; atherosclerosis; dermatan sulphate proteoglycans; extracellular matrix