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Subendothelial retention of atherogenic lipoproteins in early atherosclerosis

Abstract

Complications of atherosclerosis are the most common cause of death in Western societies1. 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 factors2. 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 atherogenesis3. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins4. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans5. 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.

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Figure 1: Distribution of cholesterol.
Figure 2: Effect on aorta of an atherogenic diet in transgenic mice.
Figure 3: Plate-assay analysis of the ability of recombinant LDL to interact with biglycan.

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Acknowledgements

We thank L. Lindgren, C. Ullström and A. Lidell for technical assistance, O. Nerman and K. Wiklander for statistical analysis, D. Schwenke for advice with retention studies. K. Weisgraber for comments on the manuscript, and S. Ordway and G. Howard for editorial assistance. This work was supported by the Swedish Medical Research Council, The Swedish Foundation for Strategic Research, The Swedish Heart–Lung Foundation, and in part by a National Institutes of Health grant..

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Correspondence to Jan Borén.

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Skålén, K., Gustafsson, M., Rydberg, E. et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417, 750–754 (2002). https://doi.org/10.1038/nature00804

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