Abstract Background Aberrant glycosylation is a hallmark of cancer, but its relevance in atherosclerosis remains largely unexplored. One of the main types of glycosylation process is the attachment of sialic acid (SA), which is regulated by sialyltransferases and sialidases. The most well-described sialyltransferase is ST6 beta-galactoside alpha-2, 6-sialyltransferase 1 (ST6Gal1), which adds SA in an α2-6 linkage to galactose residues on N-glycans. Purpose Given the involvement of SA in multiple atherosclerotic mechanisms, our goal is to uncover the role that ST6Gal1 plays in the progression of this disease. Methods ST6Gal1 mRNA expression was assessed in human atherosclerotic plaques and in human macrophages by RT-qPCR. Mice with specific deficiency of ST6Gal1 in vascular smooth muscle cell (VSMC) or myeloid cells were generated by crossing ST6Gal1 -/- flox mice with SM22-cre or LysM-cre mice, respectively. C57BL/6J mice with VSMC (SM22 cre) - or myeloid (LysM cre) -specific ST6Gal1 deletion were injected with 1×10¹1 vector genomes of pAAV/D377Y-mPCSK9AAV-PCSK9 and fed a high-cholesterol diet for 15 weeks. Lesion size and extension was assessed by Oil Red O staining of the aortic root, while plaque morphology and composition were assessed by Sirius red (% of collagen and necrotic core) or immunofluorescence (% of CD68 and smooth muscle actin-SMA-). Results ST6Gal1 mRNA expression was decreased in human atherosclerotic plaques as compared to control healthy aortas, as well as in human macrophages stimulated with oxidized LDL. VSMC-specific deletion of ST6Gal1 showed no differences in atherosclerotic lesion size or composition compared with their corresponding control mice. In contrast, ST6Gal1 deficiency in myeloid cells lead to increased atherosclerotic size and extension, along with higher % of necrotic core and of CD68+cells. No differences were observed for collagen or SMA content. Conclusions ST6Gal1 deficiency in myeloid cells induces plaque progression and instability by increasing macrophage infiltration. Whether increasing ST6Gal-1 expression or activity in myeloid cells would be a potential therapeutic option in atherosclerosis, deserves further studies.
Galvez et al. (Fri,) studied this question.