Subendothelial retention of atherogenic lipoproteins in early atherosclerosis

Abstract

Complications of atherosclerosis are the most common cause of death in Western societies. Among the many risk factors identified by epidemiological studies, only elevated levels of lipoproteins containing apolipoprotein (apo) B can drive the development of atherosclerosis in humans and experimental animals even in the absence of other risk factors. However, the mechanisms that lead to atherosclerosis are still poorly understood. We tested the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans. Here we present direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins (LDL) is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wild-type control LDL. We conclude that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.

Diabetic dyslipidaemia: from basic research to clinical practice*

“…Recent data suggest that apo B 48 and apo B 100 containing lipoproteins are probably equally atherogenic [96]. Both apoproteins can bind effectively to proteoglycans, the former via a newly identified binding segment of apo B 48 masked in apo B 100 [96] and the latter via a different domain [97]. In concert postmeal metabolic excursions comprise a cluster of potentially highly atherogenic perturbations that could be more important in terms of damaging the arterial wall than those due to hyperglycaemia [76].…”

“…The conformation of apo B 100 is distinct between the LDL subspecies and this is reflected in the different exposure of apo B 100 on the surface of LDL particles. The key difference is that specific segments which mediate the binding of apo B 100 to proteoglycans are exposed on the surface of small dense LDL particles [96,97,101,103].…”

Apolipoprotein B in Cholesterol-Containing Drusen and Basal Deposits of Human Eyes with Age-Related Maculopathy

“…25 Reduced apo B binding to intimal proteoglycans markedly attenuates atherosclerosis in mice. 26 Apo B is a large and intensively studied protein with globular and ␣-helical amphipathic domains and ␤-sheets. 27 Apo B-100 (4536 residues) is produced in the liver, where it is assembled into very low density lipoproteins before secretion into plasma.…”

Oxidized Low Density Lipoprotein (LDL) Affects Hyaluronan Synthesis in Human Aortic Smooth Muscle Cells

“…LDL retention at the subendothelial level is one of the first events triggering atherosclerosis, with the concurrent involvement of SMC for the disease onset and progression (20,41). It has been shown that, together with macrophages, AoSMC overloaded with cholesterol contribute to foam cell formation (21), highlighting the emerging role of this cell type in early atherosclerosis.…”