The role of CYP19A1, ESR1 and MIF genes polymorphims on the angiographic severity and the extent of atherosclerotic coronary artery disease

Conclusions: Linagliptin therapy improved glucose tolerance but had no additional effects on atherosclerotic plaque inflammation determined by 18F-FDG uptake in IGF-II/Ldlr-/-Apob100/100 mouse model.

Acknowledgements: Linagliptin was provided by Boehringer Ingelheim as part of the SUMMIT/ENSO project (GA 115006), funded by the Innovative Medicines Initiative Joint Undertaking.

PO032.

THE ROLE OF CYP19A1, ESR1 AND MIF GENES POLYMORPHIMS ON THE ANGIOGRAPHIC SEVERITY AND THE EXTENT OF ATHEROSCLEROTIC CORONARY ARTERY DISEASE

Neslihan Coban1_{, Aysem Kaya}2_{, Aycan Fahri Erkan}3_{, Filiz Guclu-Geyik}1_, Berkay Ekici3_{, Evin Ademoglu}2_{, Irem Yagmur Diker}1_{, Gunay Can}4_{, Nihan} Erginel-Unaltuna1_. 1_{Department of Genetics, Institute for Experimental}

Medicine, Istanbul University, Istanbul, Turkey; 2_{Departments of}

Biochemistry Laboratory, Institute of Cardiology, Istanbul University, Istanbul, Turkey; 3_{Department of Cardiology, Medical Faculty, Ufuk}

University, Ankara, Turkey; 4_{Cerrahpasa Medical Faculty, Department of}

Public Health, Istanbul University, Istanbul, Turkey

Aim: Coronary artery diseases (CAD) is one of the most important public health problems in Turkish population. Molecular pathogenesis underly-ing CAD is not fully known yet. Therefore, it is important to identify polymorphisms of the candidate genes critical in the development and treatment of this disease. Here, we focused on the three atherosclerosis related genes namely, ESR1, CYP19A1 and MIF.

Methods: Selected 332 Turkish CAD (coronary lesion with 70-100% ste-nosis) patients and controls (coronary lesion with<30 % stenosis) were genotyped for MIF-173 G/C, CYP19A1 rs10046 C/T and ESR1 rs2175898 A/G polymorphisms using hybridization probes in Real-Time PCR LC480 device. Blood samples were drawn before coronary angiography. Gensini and SYNTAX scores and myocardial blush grade (MBG) were assessed. Results: While CYP19A1 CC genotype disclosed lower values for LDL-C (p<0.05) in CAD, HDL-C (p<0.05) was significantly higher among non-CAD with ESR1 GG genotype. In addition, significant association (p¼0.05) existing between ESR1 GG genotype and HbA1C was confined to CAD group. In addition, MIF CC genotypes in CAD groups was marginally sig-nificant for HbA1C (p¼0.068). Logistic regression analysis showed ESR1 GG genotype tend to predict CAD risk (OR¼ 5.8; [95% Cl 1.07e31.3]), additively to age, BMI, fasting glucose and adiponectin in women, but not in men. In addition, CYP19A1 rs10046 C/T polymorphism was significantly associated with SYNTAX score (p¼0.05).

Conclusions: The CYP19A1 rs10046 and ESR1 rs2175898 polymorphisms were associated with CAD and CAD risk factors such as LDL-C, HDL-C and insulin resistance.

PO033.

EFFECT OF BILE ACID RECEPTOR (FXR/TGR5) AGONIST INT-767 ON PERIPHERAL IMMUNE CELLS

Zuzana Papackova, Marie Heczkova, Helena Dankova, Monika Cahova. Institute for Clinical and Experimental Medicine, Prague, Czech Republic Aim: Bile acids (BA) are potent signaling molecules that, through activa-tion of nuclear receptor, farnesoid X receptor (FXR) and the membrane G protein-coupled receptor TGR5 modulate BA homeostasis, inflammation, and lipid and glucose metabolism. It has recently showed that pharma-cological dual activation TGR5 and FXR plays significant role in prevention of atherosclerosis progression and this activation of BA receptors may be promising targets for treatment of both liver and metabolic disease. Total parenteral nutrition (TPN) administration is strongly associated with chronic inflammation and disturbances in BA metabolism in patients. We tested hypothesis that basal and pro-inflammatory activated status of circulating monocytes in parenteral nutrition-associated liver disease (PNALD) could be affected by BA receptor (FXR/TGR5) agonist (INT-767). Methods: Monocytes were isolated from peripheral blood using Percoll gradient to get peripheral blood mononuclear cell (PBMC) fraction. CD14+ monocytes were purified using magnetic cell separation system with

negative selection kit. Isolated monocytes were stimulated with macro-phage- colony stimulating factor (M-CFS, 50 ng/ml) for 6 day to differen-tiate to macrophages. These cells were incubated for 6 hours with LPS (100 ng/ml) and with or without INT-767 (1, 10, 100

m

M). After this period we determined mRNA expression of TNF

a

, IL-1

b

, IL-8 and TNF

a

production. Results: We normalize the protocol for monocyte isolation with low contaminated proceeds. These monocytes incubated with INT-767 decrease TNF

a

production and dual stimulation of FXR/TGR5 reduced mRNA expression of pro-inflammatory cytokines.

Conclusions: These results suggest that INT-767 could be potential anti-inflammatory agent.

Supported by grant no. NV15-28745A AZV MZ CR.

PO034.

PALMITOYLETHANOLAMIDE PROMOTES ANTI-INFLAMMATORY PHENOTYPE OF MACROPHAGES AND ATTENUATES PLAQUE FORMATION IN APOE-/-MICE

Petteri Rinne1,2_{, Raquel Quillamat-Prats}1_{, Martina Rami}1_{, Larisa Ring}1_, Sabine Steffens1.1Institute for Cardiovascular Prevention (IPEK), Munich, Germany;2_{University of Turku, Turku, Finland}

Aim: The endogenous fatty acid amide palmitoylethanolamide (PEA) is a lipid-derived mediator, which does not bind to the cannabinoid receptors CB1 and CB2, but exerts potent anti-inflammatory effects by ligating

type-a

peroxisome proliferator-activated receptors (PPAR-

a

). PEA has shown to possess therapeutic potential in inflammatory disease models, but the role of PEA and its promise as a therapeutic agent in atherosclerosis remain unexplored. We aimed to evaluate the therapeutic potential of chronic PEA treatment in atherosclerotic mice.

Methods: 6-8 week-old female apoliporotein E deficient (ApoE-/-) mice were treated with either vehicle or PEA (3 mg/kg/day) for 4 weeks starting from the onset of high-fat diet or after 12 weeks on high-fat diet to study the effects of PEA on early and pre-established atherosclerosis. Lesion size and composition of plaques were determined in aortic root sections, and tissue cytokine expression was profiled by quantitative PCR.

Results: Without affecting body weight or plasma cholesterol level, chronic PEA treatment reduced atherosclerotic lesion size in both early and advanced stages of the disease (by 34% and 32%, respectively). Absolute macrophage-positive area of the lesions was similarly reduced in PEA-treated mice. In terms of aortic gene expression, PEA treatment down-regulated M1-type macrophage markers and pro-inflammatory adhesion molecules while enhancing the expression of M2-type macrophage markers.

Conclusions: Our data show that PEA has therapeutic effects in models of early and advanced atherosclerosis by limiting plaque inflammation and by promoting the anti-inflammatory M2-type phenotype of macrophages. PO035.

LIPIDS TRIGGER LOCAL MACROPHAGE PROLIFERATION IN MICE Ingo Hilgendorf, Carmen H€ardtner, Jiadai Zou, Alina Jander, Jan Kornemann, Bianca Dufner, Natalie Hoppe, Christoph Bode, Andreas Zirlik. University Heart Center Freiburg, Freiburg, Germany

Aim: Background: Local proliferation dominates macrophage turnover in advanced atherosclerotic lesions. Here we investigate whether modifying lipid metabolism influences local macrophage proliferation.

Methods: Quantifying lesional macrophage proliferation in mixed bone marrow chimeras using knockouts of cholesterol im- and exporters and following statin treatment.

Results: Scavenger receptor A and B deficiency significantly decreased lesional macrophage proliferation in LDLR-deficient mixed bone marrow chimeras as assessed by Ki67 expression while apoptosis remained un-changed. In contrast cholesterol exporter deficient lesional macrophages showed increased proliferation. Finally, statin induced cholesterol lowering in mice reduced macrophage proliferation in established atherosclerotic plaques.

Abstracts / Atherosclerosis 263 (2017) e111ee282 e120