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2017 Cardiovascular Research Day Abstract Book

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84<br />

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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