2017 Cardiovascular Research Day Abstract Book
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Reduced Low-Density Lipoprotein Receptor-Related Protein-1 in Mature Mice Modestly<br />
Effects Hypercholesterolemia and Atherosclerosis<br />
Shayan Mohammadmoradi, MS 1 • Deborah A. Howatt 1 • Anju Balakrishnan 1 • Jessica<br />
J. Moorleghen 1 • Mark Graham 2 • Adam Mullick 2 • Hong Lu, PhD 1 • Alan Daugherty, PhD, DSc 1<br />
1Saha <strong>Cardiovascular</strong> <strong>Research</strong> Center, University of Kentucky • 2 Ionis Pharmaceuticals<br />
Graduate Student<br />
Background and Objectives:<br />
Low-density lipoprotein receptor-related protein-1 (LRP1) has been hypothesized to serve as a<br />
receptor for the removal of selected lipoprotein particles from plasma. However, mice with<br />
somatically engineered mutation of LRP1 have not provided a clear understanding of the specific<br />
lipoprotiens that are regulated by LRP1. Therefore, the aim of this study was to reduce LRP1 using<br />
antisense oligomers in mature mice to determine effects on lipoprotein metabolism and<br />
atherosclerosis.<br />
Methods and Results:<br />
LRP1 antisense oligonucleotide (ASO; 50 mg/kg, injected once per week) or its control ASO was<br />
administered subcutaneously to 8-week old male low-density lipoprotein (LDL) receptor deficient<br />
mice (n=10/each group). All groups were fed a saturated fat-enriched diet for 8 weeks started 1<br />
week after the first injection of ASOs. There was no difference in body weight between the two<br />
groups. Profound reduction of LRP1 was confirmed by qPCR and Western blotting. Whole body<br />
inhibition of LRP1 elicited a modestly increased total plasma cholesterol compared to its control<br />
group. Size exclusive chromatography analyses demonstrated the increased cholesterol was due to<br />
increased VLDL and LDL-cholesterol. Despite augmented hypercholesterolemia, whole body<br />
inhibition of LRP1 did not increase atherosclerotic lesion size. LRP1 was also reduced in a<br />
hepatocyte-specific manner by administration of an LRP1 ASO coupled with GalNac to target the<br />
asialofeutin receptor. LDL receptor deficient mice were injected with GalNAc LRP1 ASO or its<br />
control ASO (5 mg/kg/week). Hepatic-specific inhibition of LRP1 did not change plasma cholesterol<br />
concentration, lipoprotein distribution and atherosclerosis.<br />
Conclusion:<br />
Profound reductions of LRP1 in mature mice modestly increased hypercholesterolemia and had no<br />
effect on atherosclerosis in LDL receptor deficient mice.<br />
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