APOLIPOPROTEIN-E MODULATES LOW-DENSITY-LIPOPROTEIN RETENTION BY LIPOPROTEIN-LIPASE ANCHORED TO THE SUBENDOTHELIAL MATRIX

Lipoprotein lipase (lipase), a key enzyme in lipoprotein triglyceride metabolism, has been shown to markedly increase low density lipoprotei n (LDL) retention by subendothelial matrix. In the present study we as sessed the role that lipoprotein and matrix components play in retenti on of LDL by lipase anchored to the subendothelial matrix. Lipase addi tion to subendothelial matrix increased LDL retention by 66-fold. Scat chard analysis of LDL binding to lipase-containing matrix yielded an a ssociation constant of 12 nm. Exogenous addition of the matrix compone nts, heparan sulfate and dermatan sulfate (i.e. chondroitin sulfate B) , reduced LDL retention by greater than 90%. These glycosaminoglycans (GAGs) also reduced lipolytic activity associated with the matrix, sug gesting that lipase was released from its binding sites on the matrix. In contrast, other matrix components (collagen, fibronectin, vitronec tin, and chondroitin sulfate A) neither affected LDL release nor matri x lipolytic activity. Thus, heparan sulfate and dermatan sulfate funct ion to anchor lipase to the subendothelial cell matrix. The effects of apolipoprotein E (apoE) and apoA-I were also examined. Preincubation of the subendothelial matrix with apoE, followed by washing, did not a ffect subsequent lipase binding to the matrix nor its ability to retai n LDL. However, the direct addition of apoE alone or in combination wi th phospholipid liposomes decreased lipase-mediated LDL retention in a concentration-dependent fashion. Addition of apoA-I had no effect. Th us, in these studies apoE functions to displace LDL bound to lipase, b ut not lipase anchored to the matrix. To further examine the physiolog ic implications of this process, we assessed the ability of human apoE -rich and apoE-poor high density lipoproteins (HDL) to displace LDL fr om matrix-anchored lipase. ApoE-rich HDL reduced LDL retention dramati cally (86% at 2.5 mug/ml). In contrast, apoE-poor HDL, at the highest concentration evaluated (400 mug/ml), decreased LDL retention by only 32%. Overall, these data suggest apoE and specifically apoE-containing HDL reduce the lipase-mediated retention of LDL by subendothelial mat rix. This observation, in part could explain the protective effects of apoE and apoE-containing HDL against atherosclerosis.