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2017 Cardiovascular Research Day Abstract Book

69 Fish oil-derived

69 Fish oil-derived long-chain monounsaturated fatty acid (LCMUFA) for cardiovascular diseases : a novel approach for cardioprotection Zhihong Yang, PhD 1 • Scott Gordon, PhD 1 • Milton Pryor 1 • Shuibang Wang, PhD 2 • Robert Danner, MD, PhD 2 • Alan Remaley, MD, PhD 1 1Lipoprotein Metabolism Section, CPB/NHLBI, National Institutes of Health • 2 Critical Care Medicine Department, Clinical Center, National Institutes of Health Postdoc Cardiovascular disease (CVD) remains the leading cause of death, disability, and healthcare expense in the United States and is also a major healthcare problem worldwide. Numerous studies have shown cardiovascular benefits of fish oil, and most of these favorable effects have been attributed to omega-3 fatty acids. Fish oils, however, also contain varying amounts of other unusual types of fatty acids not commonly found in other food sources. For example, oils derived from saury, pollock and herring are all enriched in long-chain monounsaturated fatty acids (LCMUFA) with aliphatic tails longer than 18 C atoms (i.e., C20:1 and C22:1 isomers combined). Compared with well-studied omega-3, limited information is available on the role of LCMUFA in cardiovascular health. In the current study, we first examined the effect of saury fish oil-derived LCMUFA concentrate on the pathogenesis of atherosclerosis in atherosclerosis animal model. In LDLR-deficient female mice, we observed that 12-week supplementation of 2% LCMUFA on a western diet significantly decreased atherosclerosis lesion areas and accumulation of macrophages, compared with western diet (control) or western diet supplemented with 2% olive oil enriched in shorter-chain MUFA oleic acid (C18:1 n-9), although there were no differences in plasma lipoprotein profiles between the three groups. LCMUFA diet also decreased plasma inflammatory cytokine levels, and improved cholesterol efflux capacity to apoB-depleted plasma in BHK cells overexpressing ABCA1. RNA sequencing and subsequent qPCR analyses revealed that LCMUFA upregulated hepatic PPAR signaling pathway. To clarify the individual effect of LCMUFA isomers, we further produced concentrated C20:1 and C22:1 fractions, and fed LDLR-deficient mice a western diet supplemented with 5% C20:1, C22:1, or not (control) for 12 weeks. In good agreement with the first study, both LCMUFA isomers showed beneficial effects on atherosclerosis development, systematic inflammation, and cholesterol efflux capacity, without lowering plasma lipids. It is suggested that the atheroprotective effect of LCMUFA is likely due to both isomer fractions. Alterations in lipoprotein proteome revealed by LC-MS/MS proteomic analysis were favorably correlated with reduction in atherosclerotic plaque areas. For mechanistic study, we hypothesized that some of the beneficial effect of LCMUFA were derived from their metabolite, and we synthesized LCMUFAderived ethanolamides to estimate their effect on PPAR activation. In vitro PPAR transactivation assay revealed a beneficial role of LCMUFA-derived ethanolamides in PPAR transcriptional activity. Based on these positive findings, we are now conducting a double-blind crossover clinical trial of LCMUFA-rich saury oil to estimate the effect of LCMUFA-rich diet on lipoprotein metabolism in adults (ClinicalTrials.gov Identifier: NCT03043365). In conclusion, our research showed for the first time that fish oil-derived LCMUFA-rich diet attenuates atherosclerosis, possibly by regulating PPAR signaling pathway and modulating lipoprotein proteome, other than lipid-lowering effects. Although omega-3 fatty acids are generally considered the major active components in fish lipids, our findings provide novel insights into potential cardioprotective effect of LCMUFA-rich fish oil, and build on past efforts to understand the impacts of MUFA on health outcomes. 85

70 Hypercholesterolemia-induced endothelial dysfunction is rescued by overexpression of endothelial Kir2.1 in resistance arteries Ibra Fancher, PhD 1 • Sang Joon Ahn, PhD 2 • Crystal Adamos 3 • Catherine Osborn 3 • Catherine Reardon, PhD 4 • Godfrey Getz, MD, PhD 4 • Shane Phillips, PhD 3 • Irena Levitan, PhD 3 1Medicine, University of Illinois at Chicago • 2 Yale University • 3 University of Illinois at Chicago • 4University of Chicago Postdoc Rationale: Hypercholesterolemia induces endothelial dysfunction, a key stage in the development of cardiovascular disease. Impairment of nitric oxide (NO) dependent vasomotor function is established as an important factor. We recently identified endothelial Kir2.1 as upstream mediators of flow-induced NO production. Our earlier studies established that endothelial Kir is suppressed by cholesterol. Objective: We tested the hypothesis that hypercholesterolemia induces microvascular endothelial dysfunction through suppression of Kir2.1, which we propose to be responsible for the inhibition of flow-induced NO production and the loss of NO-dependent component of flow-induced vasodilation (FIV). Methods and Results: Kir2.1 currents and their sensitivity to flow are significantly suppressed in microvascular endothelial cells exposed to acetylated-LDL without any change in Kir2.1 expression. Genetic deficiency of Kir2.1 on the background of hypercholesterolemic Apoe-/- mice, Kir2.1+/- /Apoe-/- exhibit the same blunted FIV and flow-induced NO response as Apoe-/- and Kir2.1+/- alone, as we showed earlier Kir2.1+/- arteries show significant impairment of (FIV) and NO production. Endothelial-specific overexpression of Kir2.1 via adenoviral transduction of arteries from Apoe-/- and Kir2.1+/-/Apoe-/- mice results in full rescue of FIV and NO production in both hypercholesterolemic models. Conversely, endothelial-specific expression of dominant-negative Kir2.1 results in impairment of FIV in WT arteries but has no further effect on the blunted FIV in Apoe-/- arteries. No differences were detected in Kir2.1 or eNOS expression between WT and Apoe- /- mice. Notably, a full rescue of the FIV response by endothelial-specific Kir2.1 was observed in Apoe-/- mice with and without the addition of high fat diet. Conclusions: We conclude that hypercholesterolemia-induced reduction in FIV is largely attributable to cholesterol suppression of Kir2.1 function via the loss of flow-induced NO production. The stages downstream of flow-induced Kir2.1 activation appear to be intact because overexpression of endothelial Kir2.1 rescues FIV and flow-induced NO production in arteries from hypercholesterolemic mice. 86

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