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2017 Cardiovascular Research Day Abstract Book

25 Myeloid β-catenin

25 Myeloid β-catenin deficiency exacerbates atherosclerosis in low-density lipoprotein receptor-deficient mice Fang Wang, PhD 1 • Zun Liu, PhD 1 • Se-Hyung Park, PhD 1 • Taesik Gwag, PhD 1 • Weiwei Lu, PhD 1 • Yipeng Sui, PhD 1 • Changcheng Zhou, PhD 1 1Pharmacology and Nutritional Science, University of Kentucky Postdoc Objective: The Wnt/β-catenin signaling pathway is an ancient and evolutionarily conserved pathway regulating essential aspects of cell fate determination, proliferation, migration and polarity. Canonical Wnt/β-catenin signaling has been implicated in atherosclerosis development but the cell-specific role of β-catenin in atherogenesis remains elusive. Macrophage is one of the major cell types involved in the initiation and progression of atherosclerosis, and this study aims to investigate the impact of β-catenin expression on macrophage functions and atherosclerosis development. Methods and Results: To investigate the role of macrophage Wnt/β-catenin signaling in atherogenesis, we generated myeloid-specific β-catenin-deficient low-density lipoprotein receptordeficient mice (β-catenin∆myeLDLR-/-). As expected, deletion of β-catenin decreased macrophage adhesion and migration in vitro. However, β-catenin∆myeLDLR-/- mice had significantly increased atherosclerosis as compared with control littermates. Mechanistic studies revealed that β-catenin can directly regulate signal transducer and activator of transcription (STAT) pathway in macrophages, and ablation of β-catenin resulted in STAT1 activation, leading to elevated macrophage inflammatory responses and increased atherosclerosis. Conclusions: This study demonstrates a critical role of myeloid β-catenin expression in atherosclerosis by modulating macrophage inflammatory responses. 41

26 Vascular inflammation induced expression of lipid phosphate phosphatase Kavya Balaji 1 • Patrick Van Hoose, PhD 1 • Andrew Morris, PhD 1 • Susan Smyth, MD, PhD 1 1Cardiovascular Research Center, University of Kentucky Undergraduate Lipid phosphate phosphatase 3 (PLPP3) is a polymorphic gene that is a member of the phosphatidic acid phosphatase family. It encodes for the cell surface enzyme, lipid phosphate phosphatase 3 (LPP3) that regulates lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) availability and signaling. Genome wide association studies in humans identified heritable single nucleotide polymorphisms (SNPs) in PLPP3 that predicts coronary artery disease risk independently of traditional risk factors (odds ratio, 1.17; P=3.81×10–19). PLPP3 is dynamically regulated during vascular inflammation and the risk allele reduces gene expression by disrupting binding of CCAAT enhancer binding protein beta (CEBPβ). However, other mechanisms may control dynamic regulation of PLPP3. The USC Genome Browser identifies potential target sequences for NFκB responsive elements in the PLPP3 promoter, including three potential RelA (p65) binding sites. Hypothesis: These observations led to the hypothesis that angiotensin II, an inducer of vascular inflammation could regulate of PLPP3. Methods: Coronary human smooth muscle cells (caHSMCs) were treated for 12, 24, 48 and 72hrs hours with 1 M angiotensin II (ATII) in the presence or absence of parthenolide. Following treatment PLPP3 and p65 gene expression was examined. Results: The time course treatment of ATII revealed 72hr treatment upregulated PLPP3 gene expression in caHSMCs and this upregulation of PLPP3 was inhibited in the presence of parthenolide, an inhibitor of IκBα degradation. Conclusion: These observations suggest possible regulation of PLPP3 via an angiotensin II-NFkB dependent pathway, which may be important in the context of vascular disease. 42

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