Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 38, Pages 14689-14706Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.004589
Keywords
lipoprotein metabolism; monocyte; sialidase; atherosclerosis; glycosylation inhibitor; sialic acid; gene knockout; apolipoprotein E (ApoE); bone marrow; transplantation; Hyaluronic acid; P-selectin
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Funding
- Heart & Stroke Foundation of Canada (HSF) grants
- Canadian Institutes of Health Research (CIHR) postdoctoral fellowship
- CIHR studentship
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Atherosclerosis is a complex disease that involves alterations in lipoprotein metabolism and inflammation. Protein and lipid glycosylation events, such as sialylation, contribute to the development of atherosclerosis and are regulated by specific glycosidases, including sialidases. To evaluate the effect of the sialidase neuraminidase 1 (NEU1) on atherogenesis, here we generated apolipoprotein E (ApoE)-deficient mice that express hypomorphic levels of NEU1 (Neu1(hypo)Apoe(-/-)). We found that the hypomorphic NEU1 expression in male Apoe(-/-) mice reduces serum levels of very-low-density lipoprotein (VLDL) and LDL cholesterol, diminishes infiltration of inflammatory cells into lesions, and decreases aortic sinus atherosclerosis. Transplantation of Apoe(-/-) bone marrow (BM) into Neu1(hypo)Apoe(-/-) mice significantly increased atherosclerotic lesion development and had no effect on serum lipoprotein levels. Moreover, Neu1(hypo)Apoe(-/-) mice exhibited a reduction in circulating monocyte and neutrophil levels and had reduced hyaluronic acid and P-selectin adhesion capability on monocytes/neutrophils and T cells. Consistent with these findings, administration of a sialidase inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid, had a significant anti-atherogenic effect in the Apoe(-/-) mice. In summary, the reduction in NEU1 expression or function decreases atherosclerosis in mice via its significant effects on lipid metabolism and inflammatory processes. We conclude that NEU1 may represent a promising target for managing atherosclerosis.
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