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2017 Cardiovascular Research Day Abstract Book

81 Scavenging reactive

81 Scavenging reactive aldehydes with 5'-O-pentyl-pyridoxamine (PPM) improves HDL function and reduces atherosclerosis in Ldlr deficient mice Jiansheng Huang, PhD 1 • Linda Zhang, PhD 2 • Patricia Yancey, PhD 1 • Huan Tao, PhD 1 • Lei Ding 3 • YouMin Zhang 1 • John Oates, MD 4 • Venkataraman Amarnath, PhD 5 • Jackson Roberts , PhD 2 • Sean Davies, PhD 2 • MacRae Linton, MD 4 1Medicine, Vanderbilt University Medical Center • 2 Pharmacology, Vanderbilt University • 3Vanderbilt University Medical Center • 4 Medicine and Pharmacology, Vanderbilt University Medical Center • 5 Pathobiology, Vanderbilt University Medical Center Postdoc Background: Lipid peroxidation products impair the cholesterol efflux capacity of high-density lipoprotein (HDL) and contribute to the development of atherosclerosis. The effect of inhibition of HDL dysfunction by scavengers on HDL function and whether scavenging reactive aldehydes with PPM protects against the development of atherosclerosis was examined. Methods and Results: HDL of familial hypercholesterolemia (FH) subjects has impaired ability to promote cholesterol efflux and FH-HDL contains 5-fold more malondialdehyde crosslinks (MDA- Lys) than control HDL. In vitro studies found that the reactive aldehyde malondialdehyde (MDA) crosslinks apolipoprotein AI (apoAI) and impairs the ability of HDL to promote cholesterol efflux from Apoe-/- macrophages in a MDA dose dependent manner. Western blot analysis of apoAI revealed that the reactive aldehyde scavenger 5'-O-pentyl-pyridoxamine (PPM) abolished MDAmediated crosslinking of apoA-I in HDL (at a molar ratio of MDA to HDL of 1:5) by 80% (P

82 Protease-activated Receptor 2 Deficiency Attenuates the Formation of Atherosclerosis in Mice Shannon Jones 1 • Adrien Mann 1 • Kelsey Conrad, MS 1 • Keith Saum 1 • David Hall, MS 2 • Lisa McKinney 1 • Nathan Robbins, MS 1 • Joel Thompson, PhD 3 • Abigail Peairs, PhD 2 • Michael Tranter, PhD 1 • Nigel Mackman, PhD 4 • A. Phillip Owens III, PhD 1 1Internal Medicine, University of Cincinnati • 2 Nutritional Sciences, University of Cincinnati • 3Endocrinology and Molecular Medicine, University of Kentucky • 4 Medicine, UNC Chapel Hill Staff Objective – Protease-activated receptor 2 (PAR2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. While PAR2 is present in coronary atherosclerotic lesions, the relevance of this finding has not been investigated in experimental models. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. Approach and Results – PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively. To determine the effect of PAR2 deficiency on atherosclerosis, male low density lipoprotein receptor deficient (Ldlr-/-) mice (8-12 weeks old) that were Par2+/+ or Par2-/- were fed a fat and cholesterol-enriched diet for 12 or 24 weeks. PAR2 deficiency attenuated atherosclerosis in the aortic sinus and aortic root after 12 and 24 weeks. PAR2 deficiency did not alter total plasma cholesterol concentrations or lipoprotein distributions. Bone marrow transplantation showed that PAR2 on non-hematopoietic cells contributed to atherosclerosis. PAR2 deficiency significantly attenuated levels of the chemokine monocyte chemoattractant protein 1 (MCP-1) in the circulation and macrophage content in atherosclerotic lesions. Mechanistic studies using ex vivo vascular smooth muscle cells showed that PAR2 deficiency is associated with reduced production of MCP-1 mRNA and protein release into the supernatant resulting in less monocyte migration and infiltration. Conclusions – Our results indicate PAR2 deficiency is associated with attenuation of atherosclerotic inititation and reduces lesion progression by blunting MCP-1 induced monocyte infiltration. 98

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