MARKED ALTERATION OF PROTEOGLYCAN METABOLISM IN CHOLESTEROL-ENRICHED HUMAN ARTERIAL SMOOTH-MUSCLE CELLS

To elucidate the correlation between vascular cholesterol metabolism a nd proteoglycan (PrGl) biosynthesis, we investigated PrGl synthesis in human aortic smooth muscle cells (SMCs) after cholesterol enrichment with cationized low-density lipoproteins (LDL). Compared with normal S MCs, total PrGl synthesis by cholesterol-enriched cells decreased 2.4- fold (11874 +/- 530 d.p.m. per 10(5) cells compared with 4890 +/- 385 d.p.m. per 10(5) cells). This was the net result of a 6.9-fold reducti on in medium PrGl (11000 +/- 490 d.p.m. per 10(5) cells compared with 1580 +/- 246 d.p.m. per 10(5) cells) and a 3.8-fold increase in cellul ar PrGl over controls (874 +/- 27 d.p.m. per 10(5) cells compared with 3310 +/- 193 d.p.m. per 10(5) cells). Prior incubation of SMCs with n ative LDL had no effect on PrGl synthesis by these cells. The decrease in PrGl synthesis in cholesterol-enriched cells correlated with a 90% and 20% reduction in the steady-state level of mRNA for biglycan and decorin respectively, and a virtual elimination of the steady-state le vel of mRNA for versican over controls. Despite the down-regulation of PrGl synthesis, cholesterol-loaded cells produced a 2-fold increase i n a PrGl subfraction with high affinity for LDL. Compared with the cor responding PrGl subfraction from normal cells, that from the cholester ol-enriched cells exhibited increased charge density and a higher mole cular mass and contained relatively larger proportions of chondroitin 6-sulphate and dermatan sulphate. These results show that PrGl metabol ism is dramatically altered in cholesterol-enriched human SMCs.