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2017 Cardiovascular Research Day Abstract Book

53 TRAF3 negatively

53 TRAF3 negatively regulates platelet activation and thrombosis Rui Zhang, PhD 1 • Guoying Zhang, MD 1 • Binggang Xiang, MD, PhD 1 • Xiaofeng Cheng, MD, PhD 2 • Lijang Tang, MD 3 • Shaojun Shi, MD 4 • Yani Liu, MD 4 • Xun Ai, PhD 5 • Ping Xie, PhD 6 • Zhenyu Li, MD, PhD 1 1Division of Cardiovascular Medicine, University of Kentucky • 2 Taizhou Hospital, Wenzhou Medical University • 3 Department of Cardiology, Zhejiang Hospital • 4 Department of Pharmacy, Huazhong University of Science and Technology • 5 Department of Physiology and Biophysics, Rush University • 6 6Department of Cell Biology and Neuroscience, Rutgers University Faculty CD40 ligand (CD40L), a member of the tumor necrosis factor (TNF) superfamily, binds to CD40, leading to many effects depending on target cell type. Platelets express CD40L and are a major source of soluble CD40L. CD40L has been shown to potentiate platelet activation and thrombus formation, involving both CD40-dependent and -independent mechanisms. A family of proteins called TNF receptor associated factors (TRAFs) plays key roles in mediating CD40L-CD40 signaling. Platelets express several TRAFs. It has been shown that TRAF2 plays a role in CD40L-mediated platelet activation. Here we show that platelets also express TRAF3, which plays a negative role in regulating platelet activation. Thrombin- or collagen-induced platelet aggregation and secretion are increased in TRAF3 knockout mice. The expression levels of collagen receptor GPVI and integrin αIIbβ3 in platelets were not affected by deletion of TRAF3, suggesting that increased platelet activation in the TRAF3 knockout mice was not due to increased expression platelet receptors. Time to formation of thrombi in a FeCl3-induced thrombosis model was significantly shortened in the TRAF3 knockout mice. However, mouse tail-bleeding times were not affected by deletion of TRAF3. Thus, TRAF3 plays a negative role in platelet activation and in thrombus formation in vivo. 69

54 Impact of miR-33 antagonism on metabolic parameters in nonhuman primates Tara E. Keenan 1 • Tong Li, MD 1 • Lei Cai, PhD 1 • Sierra M. Paxton 1 • Courtney R. Burkett 1 • Peter I. Hecker 1 • Ryan E. Temel, PhD 1 1Saha Cardiovascular Research Center and Department of Pharmacology and Nutritional Sciences, University of Kentucky Undergraduate Introduction: MicroRNA-33a (miR-33a) and miR-33b regulate lipid homeostasis by inducing degradation or blocking translation of mRNAs encoding proteins that control cholesterol efflux and fatty acid oxidation. By stimulating macrophage cholesterol efflux and promoting antiinflammatory macrophage polarization, antagonism of miR-33a in mice reduces atherosclerotic. However, some mouse studies have shown that disruption of miR-33 function has negative metabolic effects such as increased plasma and hepatic triglycerides. Mouse studies have limited translational value since mice express only one of the two miR-33 family members found in humans. Since nonhuman primates (NHPs) have miR-33a and miR-33b, NHPs are the best preclinical model for determining the therapeutic potential of miR-33 antagonism. The objective of this project was to determine whether miR-33 antagonism has adverse metabolic effects on NHPs. Methods: Liver was collected via laparotomy from 12 chow fed male cynomolgus monkeys. Male cynomolgus monkeys (n=36) were fed for 20 months a high fat/high cholesterol diet, which caused hypercholesterolemia and atherosclerosis development. At the end of the 20-month progression phase, a subset of monkeys (n=12) were euthanized to collect tissues. The remaining monkeys were switched to a cholesterol-lowering “chow” diet and treated with either vehicle (n=12) or anti-miR- 33 (n=12) for 6 months. Blood was collected at 20 months of progression and 2, 4, and 6 months of regression and the serum was sent to ANTECH Diagnostics for chemical analysis. Liver lipid content was biochemically determined. Results: Feeding the monkeys a chow diet for 6 months caused serum triglycerides (TG) to significantly increase and total cholesterol (TC) to significantly decrease. However, serum TG and TC were similar for the vehicle and anti-miR-33 treated monkeys. The progression group had significantly greater hepatic TC and TG compared to the regression groups. Hepatic TC and TG levels of the vehicle and anti-miR-33 groups were similar and had returned to the baseline levels observed in monkeys fed only chow. In line with the liver lipids changes, serum ALT and AST levels were reduced to a similar extent in the regression NHPs. In addition, body weights and serum glucose concentrations were similar for the vehicle and anti-miR-33 treated NHPs during the 6- month regression phase. Conclusion: Metabolic parameters are normal in chow-fed NHPs treated with miR-33 antagonist. 70

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