期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 10, 期 4, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.120.018756
关键词
Ashwell‐ Morell receptor; low‐ density lipoprotein; macrophage; neuraminidase; sialic acid
资金
- Canadian Glycomics Network (Project CD-2)
- Canadian Institutes of Health Research [PJT-148863]
- Natural Sciences and Engineering Research Council of Canada
- Canada Research Chair
- Russian Science Foundation [20-15-00264]
Neuraminidases 1 and 3 play a significant role in the initial phase of atherosclerosis by desialylating LDL and increasing their uptake by resident macrophages, ultimately leading to the formation of aortic fatty streaks.
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.
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