The long term goal of the proposed studies is to improve our understanding of lipoprotein-macrophage interactions that may contribute to foam cell formation and atherogenesis. Emphasis will be placed on the acetyl LDL receptor (SRA), hCD36 and its mouse homologue (mDC36), and a 94-97 kDa oxidized LDL (OxLDL)- binding protein from mouse peritoneal macrophages which we have previously characterized and have now identified as macrosialin. Macrosialin and its human homologue, DC68, both previously clones, are found predominantly in the late endosomal fraction and their functions are not known. We propose to study their transport between subcellular compartment, to prepare stably transfected cells to characterize their ligand-binding properties, identify ligand binding sites by preparation of chimeric proteins and by site- directed mutagenesis, and prepare a mcarosialin knockout mouse to ascertain phenotypic consequences with regard to macrophage function, immune function and atherogenesis. CD36, an established OxLDL-binding receptor, functions in the binding and phagocytosis of apoptotic cells in cooperation with the vitronectin receptor and thrombospondin. We will test the hypothesis that binding of OxLDL may be modulated by interactions of this kind. Using cells from the SRA knockout mouse (gift of Dr. T. Kodama), we will assess the role of the receptor in OxLDL metabolism in vitro and in vivo. Finally, we will continue to use expression cloning in Xenopus oocytes to search for additional macrophage proteins that may participate in uptake of OxLDL or/and of damaged or apoptotic cells. Five clones have already been isolated. None of them represents either SRA, mCD36, or macrosialin. These will be sequenced and characterized.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL056989-02
Application #
6273232
Study Section
Project Start
1998-04-01
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Pechlaner, Raimund; Willeit, Peter; Summerer, Monika et al. (2015) Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with progressive atherosclerosis and incident cardiovascular disease. Arterioscler Thromb Vasc Biol 35:229-36
Huang, Wendy; Ghisletti, Serena; Saijo, Kaoru et al. (2011) Coronin 2A mediates actin-dependent de-repression of inflammatory response genes. Nature 470:414-8
Wan, Yihong; Evans, Ronald M (2010) Rosiglitazone activation of PPARgamma suppresses fractalkine signaling. J Mol Endocrinol 44:135-42
Chou, Meng-Yun; Fogelstrand, Linda; Hartvigsen, Karsten et al. (2009) Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest 119:1335-49
Bergmark, Claes; Dewan, Asheesh; Orsoni, Alexina et al. (2008) A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res 49:2230-9
Liguori, Antonio; D'Armiento, Francesco P; Palagiano, Antonio et al. (2008) Maternal C-reactive protein and developmental programming of atherosclerosis. Am J Obstet Gynecol 198:281.e1-5
Tsimikas, Sotirios; Aikawa, Masanori; Miller Jr, Francis J et al. (2007) Increased plasma oxidized phospholipid:apolipoprotein B-100 ratio with concomitant depletion of oxidized phospholipids from atherosclerotic lesions after dietary lipid-lowering: a potential biomarker of early atherosclerosis regression. Arterioscler Thromb Vasc Biol 27:175-81
Ricote, Mercedes; Glass, Christopher K (2007) PPARs and molecular mechanisms of transrepression. Biochim Biophys Acta 1771:926-35
Tsimikas, Sotirios; Brilakis, Emmanouil S; Lennon, Ryan J et al. (2007) Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events. J Lipid Res 48:425-33
Palinski, Wulf; Yamashita, Tomoya; Freigang, Stefan et al. (2007) Developmental programming: maternal hypercholesterolemia and immunity influence susceptibility to atherosclerosis. Nutr Rev 65:S182-7

Showing the most recent 10 out of 120 publications