Effects of Neuraminidase-Induced Modification of LDL in the Progression of Atherosclerosis in ApoE-Knockout Mice.

Abstract

Background and objectives: Desialylation of low-density lipoproteins (LDLs), defined as enzymatic removal of terminal sialic acids from apolipoprotein glycans, has been implicated in atherogenesis. However, its in vivo consequences remain unclear. We investigated whether sustained LDL desialylation induced by exogenous neuraminidase promotes atherogenesis in apolipoprotein E-knockout (ApoE-KO) mice under chow and Western diet conditions.

Methods: ApoE-KO mice received neuraminidase conjugated to mouse immunoglobulin G every 5 days for 6 weeks under chow or Western diet conditions (n=40 total). LDL sialic acid content, macrophage lipid loading, aortic lesion development, serum lipid profile, and markers of systemic toxicity were assessed.

Results: Repeated neuraminidase administration induced sustained LDL desialylation, as shown by reduced LDL sialic acid content. LDL isolated from neuraminidase-treated ApoE-KO mice showed increased atherogenicity, reflected by greater cholesterol and lipid accumulation in RAW264.7 macrophages compared with LDL from untreated ApoE-KO mice. Neuraminidase administration increased aortic lesion area under chow diet conditions. Under chow diet conditions, neuraminidase primarily increased LDL cholesterol levels and the LDL/high-density lipoprotein ratio, while total cholesterol remained unchanged. Diet-associated elevations in liver-related biochemical markers were not exacerbated by neuraminidase treatment, and no evidence of overt renal or hematological toxicity was observed.

Conclusions: These findings provide in vivo evidence that sustained LDL desialylation enhances LDL atherogenicity and accelerates atherosclerotic lesion development in ApoE-KO mice. Exogenous neuraminidase may serve as a useful tool for modeling chronic LDL desialylation in vivo and highlights sialylation pathways as potential targets in atherosclerosis.