Neuraminidases 1 and 3 Trigger Atherosclerosis by Desialylating Low‐Density Lipoproteins and Increasing Their Uptake by Macrophages - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of the American Heart Association Année : 2021

Neuraminidases 1 and 3 Trigger Atherosclerosis by Desialylating Low‐Density Lipoproteins and Increasing Their Uptake by Macrophages

Résumé

Background Chronic vascular disease atherosclerosis starts with an uptake of atherogenic modified low‐density lipoproteins (LDLs) by resident macrophages, resulting in formation of arterial fatty streaks and eventually atheromatous plaques. Increased plasma sialic acid levels, increased neuraminidase activity, and reduced sialic acid LDL content have been previously associated with atherosclerosis and coronary artery disease in human patients, but the mechanism underlying this association has not been explored. Methods and Results We tested the hypothesis that neuraminidases contribute to development of atherosclerosis by removing sialic acid residues from glycan chains of the LDL glycoprotein and glycolipids. Atherosclerosis progression was investigated in apolipoprotein E and LDL receptor knockout mice with genetic deficiency of neuraminidases 1, 3, and 4 or those treated with specific neuraminidase inhibitors. We show that desialylation of the LDL glycoprotein, apolipoprotein B 100, by human neuraminidases 1 and 3 increases the uptake of human LDL by human cultured macrophages and by macrophages in aortic root lesions in Apoe −/− mice via asialoglycoprotein receptor 1. Genetic inactivation or pharmacological inhibition of neuraminidases 1 and 3 significantly delays formation of fatty streaks in the aortic root without affecting the plasma cholesterol and LDL levels in Apoe −/− and Ldlr −/− mouse models of atherosclerosis. Conclusions Together, our results suggest that neuraminidases 1 and 3 trigger the initial phase of atherosclerosis and formation of aortic fatty streaks by desialylating LDL and increasing their uptake by resident macrophages.

Dates et versions

hal-03445477 , version 1 (24-11-2021)

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Ekaterina Demina, Victoria Smutova, Xuefang Pan, Anne Fougerat, Tianlin Guo, et al.. Neuraminidases 1 and 3 Trigger Atherosclerosis by Desialylating Low‐Density Lipoproteins and Increasing Their Uptake by Macrophages. Journal of the American Heart Association, 2021, 10 (4), ⟨10.1161/jaha.120.018756⟩. ⟨hal-03445477⟩
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