Retention of atherogenic lipoproteins in atherogenesis

Abstract: Atherosclerosis is the most common cause of death in the industrialized world. The diseaseis characterized by lipid accumulation and inflammation in the arterial wall, which may leadto obstruction of the blood flow. Lipoprotein retention is a key step in the pathogenesis of thedisease and it has been debated that this is the initiating step of atherosclerosis. Accumulationof lipids in the arterial wall can provoke all known features seen in atherogenesis.In this thesis we have investigated how hyperlipidemia induces the pathobiological changesthat lead to atherosclerosis. The aim was to investigate the mechanisms for lipid retention inthe initiation and progress of atherosclerosis and to elucidate the proteoglycan affinity ofmodified low density lipoprotein (LDL). First we identified site B in apolipoprotein (apo)B100 as the important feature for retention in early atherosclerosis. By creating transgenicmice expressing proteoglycan binding defective LDL we demonstrated that lipoproteinretention is an early step of atherosclerosis. This effect was abrogated by apoE, which showedthat apoE has the potential to retain lipoproteins in vivo. Furthermore, apoB48, which lackssite B, was demonstrated to contain a proteoglycan binding site in the amino-terminal. Thepresence of a proteoglycan binding site in the amino-terminal region of apoB may explainwhy apoB48- and apoB100-containing lipoproteins are equally atherogenic. In addition, theresults implicate that this site is masked in apoB100 and therefore non-functional. Theinteraction between LDL and proteoglycans can be modulated by changes in the composition(both surface and core lipids) of the particles. We identified site A in apoB100 to be responsiblefor the increased interaction with proteoglycans seen in secretory group IIA phospholipaseA2 (sPLA2) modified LDL. However, site A was dependent on site B to increase the affinityfor proteoglycans. In addition, cholesterol enriched LDL has been shown to be moreatherogenic than triglyceride-rich LDL. We demonstrated that the increased atherogenicitycould be due to an enhanced affinity for proteoglycans, which probably is dependent onconformational changes of apoB100. In the last study we investigated the lipid retention inadvanced lesions. We demonstrated an increased retention in atherosclerotic plaques, whichcould partly be explained by an alteration in the proteoglycan phenotype. In addition, wewere able to demonstrate that the retention was increased by facilitated interaction mediatedby bridging molecules including lipoprotein lipase (LpL) in the arterial wall. Finally, thepro-atherogenic effect of LpL seen in the vessel wall was shown to be dependent on its noncatalyticalfunction.Taken together, the results presented in this thesis reinforce the importance of retention ofapoB-containing lipoproteins in early and advanced atherosclerosis.

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