Title:Mouse Model of Low-density Lipoprotein Desialylation In Vivo
Volume: 33
Issue: 8
Author(s): Dmitry Kashirskikh*, Nelya Chicherina, Victor Glanz, Alexander Orekhov and Igor Sobenin
Affiliation:
- Laboratory of Molecular Genetic Modeling of Inflammation, Research Institute of General Pathology and
Pathophysiology, Moscow, Russian Federation
- Institute for Atherosclerosis Research, Moscow, Russian
Federation
Keywords:
Atherosclerosis, desialylation, neuraminidase, low-density lipoproteins, desLDL, sialic acid.
Abstract:
Background: Atherosclerosis is a chronic disease characterized by the increased
infiltration and retention of LDL particles in arterial walls. There are several
mechanisms underlying atherogenesis, with the pro-atherogenic modifications of LDL
playing a significant role. One such modification of native LDL is desialylation, which
is characterized by the removal of terminal sialic acid from ApoB-100 glycans that induces
critical changes in the overall functionality of the LDL particle.
Aims: The aim of this study was to model the desialylation of native LDL in mice, resembling
a phenomenon previously observed in atherosclerotic patients.
Objective: LDL desialylation was induced in C57BL/6J mice via the injection of exogenous
neuraminidase. The degree of LDL desialylation and its duration were assessed.
The impact of LDL desialylation on blood lipid levels was evaluated. Furthermore, the
morphological alterations in the aorta during LDL desialylation in the bloodstream were
examined.
Methods: The control group of C57BL/6J mice received saline injections, while the experimental
group underwent a single injection of IgG-conjugated Vibrio cholerae neuraminidase.
The LDL sialic acid levels were assessed 1-7 days post-injection using the
Warren method and normalized to total protein content measured via the Lowry method.
A similar protocol was followed for the subchronic administration of the IgG-neuraminidase
conjugate over a 6-week period. The blood lipid profiles were analyzed using commercial
kits. The atherosclerotic plaque burden in the mouse aorta was quantified using
Oil Red O and hematoxylin-eosin staining.
Results: A single administration of 20 mU IgG-neuraminidase conjugate resulted in decreased
LDL sialic acid levels for 5 days, gradually recovering by days 6-7. Subchronic
administration maintained reduced LDL sialic acid levels for up to 2 months. Notably,
sustained LDL desialylation was associated with elevated LDL cholesterol levels.
Conclusion: A sustained desialylation of LDL in C57BL/6J mice was achieved through
subchronic administration of IgG-conjugated neuraminidase. This study provides an approach
for sustained LDL desialylation in mice. Further studies using apolipoprotein E
knockout mice and LDL desialylation will reveal the role of this process in the occurrence
and development of atherosclerosis.
