Atherogenic lipoproteins and their interaction with proteoglycans

Abstract: Atherosclerosis is a multi-factorial disease and its pathogenesis is still unclear. However, accumulating evidence during recent years has led to the concept that subendothelial retention of atherogenic lipoproteins is the initiating event in atherogenesis. Subsequently, a series of biological responses to this retained material leads to specific molecular and cellular processes that promote lesion formation. Thus, clarification of the proatherogenic mechanisms by which the atherogenic lipoproteins interact with the artery wall is important to our understanding of the pathogenesis of the disease. The interaction between the atherogenic low density lipoproteins (LDL) and the artery wall involves positively charged amino acids in apolipoprotein (apo) B100, the protein moiety of LDL, that interact with the negatively charged glycosaminoglycans of the artery wall proteoglycans. The aim of this thesis was to investigate the structural elements in apoB that are important for the interaction of native and modified LDL with the artery wall proteoglycans.First we identified the proteoglycan binding site in apoB48 LDL and proposed a model that explains why this site is masked and nonfunctional in full-length apoB100-containing LDL. The presence of a proteoglycan binding site in the amino-terminal region of apoB is consistent with the response-to-retention hypothesis and may explain why apoB48- and apoB100-containing lipoproteins are equally atherogenic. We then investigated the molecular mechanism for changes in proteoglycan binding and LDL receptor affinity upon two compositional changes in LDL; cholesterol-enrichment of the core and modification by secretory group IIA phospholipase A2 (sPLA2) of the surface. The results indicate that Site A (residues 3148-3158) in apoB100 becomes functional in sPLA2-modified LDL and that Site A acts cooperatively with Site B (residues 3359-3369), the primary proteoglycan-binding site in native LDL, in the binding of sPLA2-modified LDL to proteoglycans. The results also show that cholesterol enrichment of the LDL particle is associated with increased affinity for proteoglycans and for the LDL receptor. This mechanism is likely mediated by a conformational change of Site B and is independent of Site A in apoB100. These results show that LDL affinity for proteoglycans can be modified by size-dependent effects and size-independent compositional effects of either the surface or the core. Taken together, the results presented elucidate the molecular mechanism for how atherogenic lipoproteins interact with the artery wall proteoglycans, and support the concept that subendothelial retention of apoB100-containing lipoproteins is the initiating event in atherogenesis.