Lipoprotein sialylation in atherosclerosis: Lessons from mice

Abstract

Sialylation is a dynamically regulated modification, which commonly occurs at the terminal of glycan chains in glycoproteins and glycolipids in eukaryotic cells. Sialylation plays a key role in a wide array of biological processes through the regulation of protein–protein interactions, intracellular localization, vesicular trafficking, and signal transduction. A majority of the proteins involved in lipoprotein metabolism and atherogenesis, such as apolipoproteins and lipoprotein receptors, are sialylated in their glycan structures. Earlier studies in humans and in preclinical models found a positive correlation between low sialylation of lipoproteins and atherosclerosis. More recent works using loss- and gain-of-function approaches in mice have revealed molecular and cellular mechanisms by which protein sialylation modulates causally the process of atherosclerosis. The purpose of this concise review is to summarize these findings in mouse models and to provide mechanistic insights into lipoprotein sialylation and atherosclerosis.

Sialic acid as the potential link between lipid metabolism and inflammation in the pathogenesis of atherosclerosis

“…Due to this, there was a decrease in the risk of CAD. In other studies, it was found that compared with Apoe−/− mice, NEU1 hypomorphic mice show a significantly reduced size of atherosclerotic lesions (a decrease of >50%) ( 38 ). Also, in hypomorphic NEU1 mice, fewer T cells, macrophages, and smooth muscle cells were found in the aortic root.…”

“…During CAD, ST activity in the intima and blood plasma was increased. The sialic acid level on the cell surface in vitro immediately decreased when the endothelial cell was damaged ( 44 ). After 24 h, it increased, which corresponded to an increased content of ST.…”

Atherosclerosis originating from childhood: Specific features

“…The desialylated LDL subfraction triggers the production of proatherogenic IgG auto-antibodies, leading to an increased uptake of LDL by aortic cells and potentially contributing to atherogenesis [ 25 ] . Furthermore, the presence of anti-LDL antibodies in the bloodstream results in the formation of cholesterol-containing circulating immune complexes with atherogenic properties, emphasizing the significant proatherogenic potential of these antibodies; and the characteristics of LDL extracted from immune complexes are similar to desialylated LDL, including a smaller size, a higher density and electronegative charge, a reduced sialic acid content, the elevated levels of oxysterols, and a comparable lipid peroxide content [ 26 ] .…”

“…In addition to serum sialidase, which plays a key role in enzymatically removing sialic acid from LDL, oxidative stress associated with atherosclerosis also leads to a non-enzymatic desialylation, resulting in the desialylated LDL with the reduced antioxidants, an accelerated degradation, and a modified apoB, increasing its proatherogenic potential [23] . Desialylated LDL not only impairs reverse cholesterol transport but also inhibits cholesterol-esterifying activity, while inflammation up-regulates galactose-specific lectins in macrophages, promoting the uptake of desialylated LDL [24] .…”