Lipoprotein modulation of subendothelial heparan sulfate proteoglycans (Perlecan) and atherogenicity

Heparan sulfate proteoglycans (HSPGs) are key constituents of subendothelia l extracellular matrix that play an important role in the assembly and stru cture of the basement membrane, regulation of basement membrane permeabilit y, growth factor activity and cellular adhesion. Vascular HSPGs decrease du ring inflammation, atherosclerosis and diabetes. Recent studies showed that HSPGs are negatively regulated by atherogenic molecules and positively reg ulated by antiatherogenic agents. Extracellular matrix HSPG, perlecan, appe ars to be a key target of regulation by these agents. At least two levels o f regulation appear to control perlecan HSPG in matrix, a change in core pr otein expression or a change in heparan sulfate metabolism. Atherogenic lev els of low-density lipoprotein (LDL), oxidized LDL and lysolecithin decreas e not only perlecan core protein synthesis but also enhance heparan sulfate degradation by stimulating endothelial secretion of heparanase. ApoE and a poE-HDL, in contrast, increase perlecan core protein as well as sulfation o f heparan sulfate. increased perlecan in endothelial cells was associated w ith increased antithrombin-binding and antiproliferative heparan sulfates. Moreover, modulation of perlecan appears to have a direct effect on smooth muscle cell growth. Thus, lipoprotein modulation of vascular perlecan may p lay a key role in the modulation of atherogenesis. (Trends Cardiovasc Med 2 000;10:60-65). (C) 2000, Elsevier Science Inc.