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11 months ago

2017 Cardiovascular Research Day Abstract Book

93 Impact of miR-33

93 Impact of miR-33 antagonism on atherosclerotic plaque size and cholesterol content in nonhuman primates Tong Li, MD 1 • Lei Cai, PhD 1 • Sierra Paxton 1 • Courtney Burkett 1 • Peter Hecker, MS 1 • Ryan Temel, PhD 1 1CVRC, University of Kentucky Graduate Student Introduction: Elevated LDL cholesterol (LDL-C) is a major risk factor for coronary heart disease (CHD). Statins are used to lower LDL-C and CHD risk but do not completely eliminate CHD events caused by atherosclerotic lesion rupture. By stimulating macrophage cholesterol efflux and promoting anti-inflammatory macrophage polarization, antagonism of microRNA-33a (miR-33a) in mice reduces the cholesterol content and size of atherosclerotic lesions. Mouse studies have limited translational value since mice do not develop coronary artery atherosclerosis and express only one of the two miR-33 family members found in humans. Since nonhuman primates (NHPs) have miR- 33a and miR-33b and develop coronary artery atherosclerosis, NHPs are the best preclinical model for determining the therapeutic potential of miR-33 antagonism. We hypothesize that NHPs treated with miR-33 antagonist will have decreased plaque size and cholesterol content. Methods: Male cynomolgus monkeys (n=36) were fed for 20 months a high fat/high cholesterol diet, which caused severe hypercholesterolemia. 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. Formalin-fixed right coronary arteries (RCA) were split into five ~3 mm sections, paraffin embedded, and cut into 5 µm slices. Lesion area, defined as the region between the lumen and internal elastic lamina, was measured for each RCA section and then averaged for each animal. Cholesterol was extracted from a section of the fixed thoracic aorta and the free and total cholesterol levels were determined by GC-FID. Esterified cholesterol (EC) = total cholesterol – free cholesterol (FC). Results: No significant difference among the progression, vehicle, and anti-miR-33 groups were observed for RCA lesion area (P=0.60) and thoracic aorta FC (P=0.24). Thoracic aorta EC was significantly increased in the progression versus the regression groups (P

94 Impact of miR-33 antagonism on coronary artery atherosclerotic plaque composition in nonhuman primates Lei Cai, PhD 1 • Tong Li, MD 1 • Sierra Paxton 1 • Courtney Burkett 1 • Peter Hecker, MS 1 • Ryan Temel , PhD 1 1CVRC, University of Kentucky Staff Introduction: Elevated LDL cholesterol (LDL-C) is a major risk factor for coronary heart disease (CHD). Statins are used to lower LDL-C and CHD risk but do not completely eliminate CHD events caused by atherosclerotic lesion rupture. By stimulating macrophage cholesterol efflux and promoting anti-inflammatory macrophage polarization, antagonism of microRNA-33a (miR-33a) in mice causes atherosclerotic lesions to acquire a more stable composition. Mouse studies have limited translational value since mice do not develop coronary artery atherosclerosis and express only one of the two miR-33 family members found in humans. Since nonhuman primates (NHPs) have miR-33a and miR-33b and develop coronary artery atherosclerosis, NHPs are the best preclinical model for determining the therapeutic potential of miR-33 antagonism. We hypothesize that miR-33a/b antagonism will stabilize coronary artery atherosclerotic plaques of NHPs. Methods and Results: Male cynomolgus monkeys (n=36) were fed for 20 months a high fat/high cholesterol diet, which caused severe hypercholesterolemia. At the end of the 20-month progression phase, the hearts from 12 animals were perfused with formalin under physiological to preserve the structure of the coronary arteries. 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. LDL-C for both treatment groups was rapidly reduced by the chow diet and returned to baseline levels by the 3rd month of the regression phase. The anti-miR-33 versus the vehicle group had a sustained and significant elevation in HDL-C that was linked to a significant increase in hepatic ABCA1, a miR-33 target. Following dissection and paraffin embedding of the right coronary arteries (RCA), 5 µm slices were analyzed by histology and immunohistochemistry (IHC). The RCA atherosclerotic lesions from both the progression and regression groups were characterized by intimal smooth muscle cell proliferation, collagen deposition, elastin degradation, and medial layer destruction. While necrotic cores were a common feature, there was a minimal amount of plaque calcification. Macrophages were found at high levels in the progression group lesions but were almost absent from the plaques of both the anti-miR-33 and vehicle groups. Conclusions and Future Directions: The qualitative histology and IHC results show that the monkeys developed RCA atherosclerotic plaques similar to early fibroatheromas observed in humans. By quantifying the area occupied by the various plaque components, we will determine whether antagonism of miR-33a/b allowed the lesions to attain a more stable composition. In addition, to determine whether anti-miR-33 changes the amount or type of macrophages in lesions, we will analyze coronary arteries from monkeys subjected to 6 weeks, as opposed to 6 months, of regression. 110

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