Abstract
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 (Neu1hypoApoe-/-). 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 Neu1hypoApoe-/- mice significantly increased atherosclerotic lesion development and had no effect on serum lipoprotein levels. Moreover, Neu1hypoApoe-/- 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.
Highlights
Atherosclerosis is a complex disease that involves alterations in lipoprotein metabolism and inflammation
neuraminidase 1 (NEU1) is implicated in the removal of sialic acid from leukocyte cell-surface adhesion molecules [14, 15, 26], and signaling in the Toll-like receptor 4 (TLR4) pathway [27, 28]
The modification of sialic acids on apolipoproteins can affect lipoprotein metabolism (29 –31), and lower LDL sialylation levels are associated with coronary heart disease in humans [18]
Summary
To determine whether sialidase plays a role locally within the atherosclerotic lesions and within the liver, we examined both NEU1 protein expression and sialidase activity in these tissues. We measured no difference in total NEU1 expression in the thoracic aorta, we observed lower NEU1 immunoreactivity in lesions of the aortic sinus and within the liver of Neu1hypoApoeϪ/Ϫ mice compared with ApoeϪ/Ϫ mice (Fig. 1, D–G). The area of SMAϩ smooth muscle cells within the media layer of the aortic root of Neu1hypoApoeϪ/Ϫ mice was significantly lower than ApoeϪ/Ϫ mice (Fig. 3, G–I) This implicates NEU1 sialidase in the development of the medial layer of the vessel wall. To determine whether sialidase expression in BM-derived cells plays a role in lipid metabolism, we measured the hepatic and serum lipid levels in the Neu1hypoApoeϪ/Ϫ mice that were transplanted with BM from ApoeϪ/Ϫ or Neu1hypoApoeϪ/Ϫ donors and fed a high-fat diet for 8 weeks. There was a significant decrease in serum total cholesterol, free cholesterol, and cholesteryl esters in the Neu1hypoApoeϪ/Ϫ mice (n ϭ 8) compared with the ApoeϪ/Ϫ mice (n ϭ 3)
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