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Background: The accumulation of lipid-laden macrophages, foam cells, within sub-endothelial intima is a key feature of early atherosclerosis. Siglec-E, a mouse orthologue of human Siglec-9, is a sialic acid binding lectin predominantly expressed on the surface of myeloid cells to transduce inhibitory signal via recruitment of SH2-domain containing protein tyrosine phosphatase SHP-1/2 upon binding to its sialoglycan ligands. Whether Siglec-E expression on macrophages impacts foam cell formation and atherosclerosis remains to be established. Methods: ApoE-deficient (apoE−/−) and apoE/Siglec-E-double deficient (apoE−/−/Siglec-E−/−) mice were placed on high fat diet for 3 months and their lipid profiles and severities of atherosclerosis were assessed. Modified low-density lipoprotein (LDL) uptake and foam cell formation in wild type (WT) and Siglec-E−/−- peritoneal macrophages were examined in vitro. Potential Siglec-E-interacting proteins were identified by proximity labeling in conjunction with proteomic analysis and confirmed by coimmunoprecipitation experiment. Impacts of Siglec-E expression and cell surface sialic acid status on oxidized LDL uptake and signaling involved were examined by biochemical assays. Results: Here we show that genetic deletion of Siglec-E accelerated atherosclerosis without affecting lipid profile in apoE−/− mice. Siglec-E deficiency promotes foam cell formation by enhancing acetylated and oxidized LDL uptake without affecting cholesterol efflux in macrophages in vitro. By performing proximity labeling and proteomic analysis, we identified scavenger receptor CD36 as a cell surface protein interacting with Siglec-E. Further experiments performed in HEK293T cells transiently overexpressing Siglec-E and CD36 and peritoneal macrophages demonstrated that depletion of cell surface sialic acids by treatment with sialyltransferase inhibitor or sialidase did not affect interaction between Siglec-E and CD36 but retarded Siglec-E-mediated inhibition on oxidized LDL uptake. Subsequent experiments revealed that oxidized LDL induced transient Siglec-E tyrosine phosphorylation and recruitment of SHP-1 phosphatase in macrophages. VAV, a downstream effector implicated in CD36-mediated oxidized LDL uptake, was shown to interact with SHP-1 following oxidized LDL treatment. Moreover, oxidized LDL-induced VAV phosphorylation was substantially lower in WT macrophages comparing to Siglec-E−/− counterparts. Conclusions: These data support the protective role of Siglec-E in atherosclerosis. Mechanistically, Siglec-E interacts with CD36 to suppress downstream VAV signaling involved in modified LDL uptake. [ABSTRACT FROM AUTHOR]

Sialic acid (Sia), the acylated derivative of the nine-carbon sugar neuraminic acid, is a terminal component of the oligosaccharide chains of many glycoproteins and glycolipids. In light of its important biological and pathological functions, the relationship between Sia and coronary artery disease (CAD) has been drawing great attentions recently. Large-scale epidemiological surveys have uncovered a positive correlation between plasma total Sia and CAD risk. Further research demonstrated that N-Acetyl-Neuraminic Acid, acting as a signaling molecule, triggered myocardial injury via activation of Rho/ROCK-JNK/ERK signaling pathway both in vitro and in vivo. Moreover, there were some evidences showing that the aberrant sialylation of low-density lipoprotein, low-density lipoprotein receptor and blood cells was involved in the pathological process of atherosclerosis. Significantly, the Sia regulates immune response by binding to sialic acid-binding immunoglobulin-like lectin (Siglecs). The Sia-Siglecs axis is involved in the immune inflammation of atherosclerosis. The generation of Sia and sialylation of glycoconjugate both depend on many enzymes, such as sialidase, sialyltransferase and trans-sialidase. Abnormal activation or level of these enzymes associated with atherosclerosis, and inhibitors of them might be new CAD treatments. In this review, we focus on summarizing current understanding of Sia metabolism and of its relevance to atherosclerosis. [ABSTRACT FROM AUTHOR]