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2017 Cardiovascular Research Day Abstract Book

47 Dietary Effects on

47 Dietary Effects on Lipoprotein-Associated Bioactive Mediators of Atherosclerosis Cody Sutphin 1 • Maria Kraemer, PhD 2 • Pan Deng, PhD 2 • Courtney Hammill, PhD 2 • Susan Smyth, MD, PhD 2 • Andrew Morris, PhD 2 1Eastern Kentucky University • 2 Cardiovascular Research Center, University of Kentucky Undergraduate Elevated circulating levels of atherogenic lipoproteins associate with increased risk of cardiovascular disease. Multiple lines of evidence implicate bioactive components of lipoprotein particles (such as oxidized phospholipids) as signaling molecules that provoke responses in blood and vascular cells that cause the development and progression of atherosclerosis. Studies from ourselves and others identify a role for the bioactive lipid mediator lysophosphatidic acid (LPA) as a proinflammatory atherogenic signal in preclinical models and clinical settings. LPA accumulates in atheromas, and mice lacking certain LPA receptors are protected from experimentally induced atherosclerosis while mice lacking the LPA degrading enzyme lipid phosphate phosphatase 3 (LPP3) exhibit accelerated atherosclerosis. These findings may explain why coronary artery disease risk is elevated in individuals with common genetic polymorphisms that decrease LPP3 expression. We hypothesized that LPA associated with low-density lipoprotein particles is sensitive to diet and enhanced by genetic hyperlipidemia. Plasma LDL-associated lipid species were analyzed in WT and LDLr-/- mice that were on either control or western diet. Mouse plasma was fractionated by sizeexclusion chromatography using a calibrated Superose 6 column to separate lipoprotein species and then analyzed by targeted and untargeted HPLC coupled mass spectrometry to identify and quantitate LPA species, as well as other lipid-class species, that were altered in LDL-containing plasma fractions. We found that circulating levels of LPA are highly sensitive to high fat feeding in mice and that genetic manipulations that reduce lipoprotein clearance (Ldlr-/-) dramatically increase circulating levels of LDL-associated LPA while reducing albumin-associated LPA. Additionally, we identified unexpected increases in a broad range of atherogenic lipoprotein particle- associated lipid species when hyperlipidemic mice are put onto a western diet. These studies provide new insights into how diet could influence coronary artery disease risk by promoting increase in atherogenic lipoprotein associated LPA. 63

48 Ticagrelor Reduces Inflammation and Mortality in a Murine Model of Sepsis and Reduces Platelet-Leukocyte Aggregates and Inflammation In Pneumonia Travis Sexton, PhD 1 • Guoying Zhang, MD 1 • Tracy Macaulay, PharmD 2 • Leigh Ann Callahan, MD 3 • Richard Charnigo, PhD 4 • Olga Vsevolozhskaya, PhD 4 • Zhenyu Li, PhD 1 • Susan Smyth, MD, PhD 2 1Cardiovascular Research Center, University of Kentucky • 2 Gill Heart and Vascular Institute, University of Kentucky • 3 Pulmonary, Critical Care & Sleep Medicine, University of Kentucky • 4Statistics, University of Kentucky Staff Background: Sepsis is a life-threatening and dysregulated response to infection that leads to numerous complications and carries substantial risk of mortality. Pneumonia is one of the most common precipitators of sepsis. Despite advances in treatment for sepsis and pneumonia, significant improvements have not been realized and high rates of cardiovascular events remain an issue. Retrospective analysis of clinical studies suggest anti-platelet therapy may improve outcomes in patients with pneumonia and sepsis. Methods: We conducted a human study with pneumonia patients (XANTHIPPE) and a murine study using a sepsis model to determine the effect of ticagrelor on inflammation, thrombosis, and lung function. Results: Among subjects with pneumonia not taking a P2Y12 antagonist at baseline, ticagrelor lowered the percent of leukocytes with attached platelets 11.75% at 24 hours compared to a 10.90% increase in placebo patients. Furthermore, ticagrelor lowered plasma IL-6 levels 83% at 24 hours compared to minimal change with placebo. Ticagrelor had a transient effect on markers for NETosis showing a significant 60% spike in MPO-NE complexes at 24 hours followed by a return toward baseline at 48 hours while placebo had no significant effect. Lung function tests also numerically improved with ticagrelor, although statistical significance was not achieved. In the murine sepsis model, disruption of the P2Y12 receptor protected against inflammatory response, lung permeability, and mortality. Conclusions: Our findings indicate a mechanistic link between platelets, leukocytes, and lung injury in settings of pneumonia and sepsis and suggest possible therapeutic approaches to reduce complications of pneumonia. 64

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