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2017 Cardiovascular Research Day Abstract Book

83 Deoxysphingolipids -

83 Deoxysphingolipids - mediators in taxane-induced peripheral neuropathy Katrin Anne Becker, PhD 1 • Anne-Kathrin Uerschels, MD 2 • Jacek Bielawski, PhD 3 • Joan Colglazier 4 • Erhard Bieberich, PhD 5 • Erich Gulbins, PhD 1 • Stefka Spassieva, PhD 5 1Molecular Biology , University of Duisburg-Essen • 2 Neurosurgery, University of Duisburg-Essen • 3Biochemistry and Molecular Biology , Medical University of South Carolina • 4 Medicine, Medical University of South Carolina • 5 Physiology, University of Kentucky Faculty Taxanes are chemotherapy drugs used in wide variety of cancers. However, there efficacy can be hindered by a major dose limiting side effect - peripheral neuropathy. Although, the clinical symptoms of taxane-induced peripheral neuropathy are well documented, the molecular mechanism is currently not well understood and there are no treatment options available. In our previous work, we have shown that in the plasma of breast cancer patients treated with taxane, the levels of minor class of lipids, the deoxysphingolipids, were associated with incidence and severity of neuropathy (Kramer et al, FASEB J, 2015). In our current study, we used a mouse model to test whether taxane treatment results in increased levels of deoxysphingolipids in the dorsal root ganglia and spinal cord. Mice were three times intraperitoneally injected with taxane. Lipids were extracted from the isolated ganglia and spinal cord and subjected to quantitative mass spectrometry analyses. We observed significant elevation of deoxysphingolipid levels only in the dorsal root ganglia. In addition, we compared in vitro in neuronal cultures, the toxic effect of deoxysphingosine, a deoxysphingolipid, and sphingosine, a structurally similar sphingolipid. Importantly, our in vitro data showed that only deoxysphingosine treatment resulted in morphological changes and toxicity in the neurons. Taken together our data suggest that in the dorsal root ganglia, the neurotoxic effect of the systemic taxane treatment is likely mediated by deoxysphingolipids. 99

84 Reduced Low-Density Lipoprotein Receptor-Related Protein-1 in Mature Mice Modestly Effects Hypercholesterolemia and Atherosclerosis Shayan Mohammadmoradi, MS 1 • Deborah A. Howatt 1 • Anju Balakrishnan 1 • Jessica J. Moorleghen 1 • Mark Graham 2 • Adam Mullick 2 • Hong Lu, PhD 1 • Alan Daugherty, PhD, DSc 1 1Saha Cardiovascular Research Center, University of Kentucky • 2 Ionis Pharmaceuticals Graduate Student Background and Objectives: Low-density lipoprotein receptor-related protein-1 (LRP1) has been hypothesized to serve as a receptor for the removal of selected lipoprotein particles from plasma. However, mice with somatically engineered mutation of LRP1 have not provided a clear understanding of the specific lipoprotiens that are regulated by LRP1. Therefore, the aim of this study was to reduce LRP1 using antisense oligomers in mature mice to determine effects on lipoprotein metabolism and atherosclerosis. Methods and Results: LRP1 antisense oligonucleotide (ASO; 50 mg/kg, injected once per week) or its control ASO was administered subcutaneously to 8-week old male low-density lipoprotein (LDL) receptor deficient mice (n=10/each group). All groups were fed a saturated fat-enriched diet for 8 weeks started 1 week after the first injection of ASOs. There was no difference in body weight between the two groups. Profound reduction of LRP1 was confirmed by qPCR and Western blotting. Whole body inhibition of LRP1 elicited a modestly increased total plasma cholesterol compared to its control group. Size exclusive chromatography analyses demonstrated the increased cholesterol was due to increased VLDL and LDL-cholesterol. Despite augmented hypercholesterolemia, whole body inhibition of LRP1 did not increase atherosclerotic lesion size. LRP1 was also reduced in a hepatocyte-specific manner by administration of an LRP1 ASO coupled with GalNac to target the asialofeutin receptor. LDL receptor deficient mice were injected with GalNAc LRP1 ASO or its control ASO (5 mg/kg/week). Hepatic-specific inhibition of LRP1 did not change plasma cholesterol concentration, lipoprotein distribution and atherosclerosis. Conclusion: Profound reductions of LRP1 in mature mice modestly increased hypercholesterolemia and had no effect on atherosclerosis in LDL receptor deficient mice. 100

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