2017 Cardiovascular Research Day Abstract Book

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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.
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