This project investigates the anti-atherogenic role of apolipoprotein E receptor 2 (apoER2) and very low- density lipoprotein receptor (VLDLR), using a partial reelin peptide (R5-6C) as a tool to activate these receptors. These studies extend our research on the pathogenesis of, and therapeutic strategies for atherosclerosis. We recently reported that activation of apoER2 and VLDLR by their natural ligands apoE and reelin in murine macrophages results in activation of disabled-1 (Dab1), upregulation of ATP-binding cassette transporter A1 (ABCA1) expression, accelerated cholesterol efflux and reduced cellular cholesterol accumulation. However a number of other investigators studying the impact of VLDLR and apoER2 on the pathogenesis of atherosclerosis noted that activation of these receptors is able to induce either pro- or anti- atherogenic effects, possibly dependent on the particular ligands and signaling pathways involved. Specifically, anti-atherogenic ligands, such as reelin, apoE and activated protein C (APC), activate a Dab1-dependent signaling pathway and inhibit cellular events that potentially contribute to inflammation and foam cell formation. In contrast pro-atherogenic ligands such as lipoproteins, neutrophil peptides and coagulation factor XI, elevate intracellular cholesterol accumulation and induce cell adhesion, possibly by activation of a p38-mediated pathway. This project is designed to define the anti-atherogenic role of VLDLR/apoER2 in vitro and in vivo, using a partial reelin peptide (R5-6C) as an agonist. We chose reelin because it exclusively binds VLDLR and apoER2. In contrast, apoE and APC are able to interact with other receptors as well as VLDLR and apoER2. Our central hypothesis is that activation of the VLDLR/apoER2-Dab1 pathway by R5-6C will upregulate anti- atherogenic molecules, down-regulate pro-atherogenic molecules, and therefore inhibit atherosclerosis development. SA1 will study the effect of R5-6C gene transfer on atherosclerosis in mouse models. Though the primary focus is atherosclerotic lesions, we will also study the effect of R5-6C gene transfer on the expression of pro- and anti-atherogenic proteins in the atherosclerotic area as well as on the level of plasma lipids/glucose. SA2 will tes a working hypothesis that R5-6C inhibits oxLP-induced adhesion of monocytes (MNCs) to endothelial cells (ECs) by activation of the apoER2/VLDLR-Dab1 pathway. An emphasis will be placed on the contribution of VLDLR/apoER2-Dab1 pathway to R5-6C-induced changes in adhesion of MNCs to ECs and the expression of endothelial anti- and pro-adhesion molecules. SA3 will test a working hypothesis that R5-6C inhibits foam cell formation by activation of the apoER2/VLDLR-Dab1 pathway. Experiments are designed to explore whether R5-6C blocks macrophage binding and uptake of lipoproteins, and whether activation of the VLDLR/apoER2- Dab1 pathway is a mechanism by which R5-6C regulates the expression of genes related to cholesterol metabolism and inhibits foam cell formation. If successful, this project will provide a scientific basis for designing VLDLR/apoER2 agonists, such as reelin mimetics, to treat atherosclerosis.
This proposal studies the protective effect of apolipoprotein E receptor-2 and very low density lipoprotein receptor against atherosclerosis. Data derived from this project will inform novel strategies for prevention and treatment of atherosclerosis-related diseases, such as coronary heart disease and stroke.
|Yang, Fang; Yang, Hong; Ramesh, Aramandla et al. (2016) Overexpression of Catalase Enhances Benzo(a)pyrene Detoxification in Endothelial Microsomes. PLoS One 11:e0162561|
|Okoro, Emmanuel U; Guo, Zhongmao; Yang, Hong (2016) Akt isoform-dependent regulation of ATP-Binding cassette A1 expression by apolipoprotein E. Biochem Biophys Res Commun 477:123-8|
|Miao, LiXia; Okoro, Emmanuel U; Cao, ZhiJan et al. (2015) High-density lipoprotein-mediated transcellular cholesterol transport in mouse aortic endothelial cells. Biochem Biophys Res Commun 465:256-61|
|Shan, Guang; Yang, Fang; Zhou, LiChun et al. (2015) Increase in Blood Glutathione and Erythrocyte Proteins Related to Glutathione Generation, Reduction and Utilization in African-American Old Women with Diabetes. J Sci Technol Environ 5:|
|Okoro, Emmanuel U; Zhang, Hongfeng; Guo, Zhongmao et al. (2015) A Subregion of Reelin Suppresses Lipoprotein-Induced Cholesterol Accumulation in Macrophages. PLoS One 10:e0136895|
|Wu, Jianhua; Xiao, Yanhong; Liu, Juang et al. (2014) Potential role of ATM in hepatocyte endocytosis of ApoE-deficient, ApoB48-containing lipoprotein in ApoE-deficient mice. Int J Mol Med 33:462-8|
|Zhou, LiChun; Yang, Hong; Okoro, Emmanuel U et al. (2014) Up-regulation of cholesterol absorption is a mechanism for cholecystokinin-induced hypercholesterolemia. J Biol Chem 289:12989-99|
|Zhou, Lichun; Yang, Dezhi; Wu, Dong Fang et al. (2013) Inhibition of endoplasmic reticulum stress and atherosclerosis by 2-aminopurine in apolipoprotein e-deficient mice. ISRN Pharmacol 2013:847310|
|Lin, Xinghua; Yang, Hong; Zhang, Hongfeng et al. (2013) A novel transcription mechanism activated by ethanol: induction of Slc7a11 gene expression via inhibition of the DNA-binding activity of transcriptional repressor octamer-binding transcription factor 1 (OCT-1). J Biol Chem 288:14815-23|
|Okoro, Emmanuel Ugochukwu; Zhao, Yanfeng; Guo, ZhongMao et al. (2012) Apolipoprotein E4 is deficient in inducing macrophage ABCA1 expression and stimulating the Sp1 signaling pathway. PLoS One 7:e44430|
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