title: Receptor-Mediated Mechanism Controlling Tissue Levels of Bioactive Lipid Oxidation Products.
abstract: BACKGROUND
  Oxidative stress is an important contributing factor in several human pathologies ranging from atherosclerosis to cancer progression; however, the mechanisms underlying tissue protection from oxidation products are poorly understood. Oxidation of membrane phospholipids, containing the polyunsaturated fatty acid docosahexaenoic acid, results in the accumulation of an end product, 2-(ω-carboxyethyl)pyrrole (CEP), which was shown to have proangiogenic and proinflammatory functions. Although CEP is continuously accumulated during chronic processes, such as tumor progression and atherosclerosis, its level during wound healing return to normal when the wound is healed, suggesting the existence of a specific clearance mechanism.
  
  
  OBJECTIVE
  To identify the cellular and molecular mechanism for CEP clearance.
  
  
  RESULTS
  Here, we show that macrophages are able to bind, scavenge, and metabolize carboxyethylpyrrole derivatives of proteins but not structurally similar ethylpyrrole derivatives, demonstrating the high specificity of the process. F4/80(hi) and M2-skewed macrophages are much more efficient at CEP binding and scavenging compared with F4/80(lo) and M1-skewed macrophages. Depletion of macrophages leads to increased CEP accumulation in vivo. CEP binding and clearance are dependent on 2 receptors expressed by macrophages, CD36 and toll-like receptor 2. Although knockout of each individual receptor results in diminished CEP clearance, the lack of both receptors almost completely abrogates macrophages' ability to scavenge CEP derivatives of proteins.
  
  
  CONCLUSIONS
  Our study demonstrates the mechanisms of recognition, scavenging, and clearance of pathophysiologically active products of lipid oxidation in vivo, thereby contributing to tissue protection against products of oxidative stress.
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: Young-Woong
authors.initials: YW
authors.lastname: Kim
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: Valentin P
authors.initials: VP
authors.lastname: Yakubenko
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: Xiaoxia Z
authors.initials: XZ
authors.lastname: West
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: Gabriel B
authors.initials: GB
authors.lastname: Gugiu
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: Kutralanathan
authors.initials: K
authors.lastname: Renganathan
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: Sudipta
authors.initials: S
authors.lastname: Biswas
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: Detao
authors.initials: D
authors.lastname: Gao
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: John W
authors.initials: JW
authors.lastname: Crabb
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: Robert G
authors.initials: RG
authors.lastname: Salomon
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.).
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Podrez
authors.affiliation: From the Department of Molecular Cardiology, Lerner Research Institute (Y.-W.K., V.P.Y., X.Z.W., S.B., D.G., E.A.P., T.V.B.) and Department of Ophthalmology, Cole Eye Institute (R.K., J.W.C.), Cleveland Clinic, OH; and Department of Chemistry, Case Western Reserve University, Cleveland, OH (G.B.G., R.K., R.G.S.). byzovat@ccf.org.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Byzova
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D010641:Phenotype; D011758:Pyrroles / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D047368:Tumor Burden; D014945:Wound Healing
chemical_list: C000602461:2-(omega-carboxyethyl)pyrrole; D000943:Antigens, Differentiation; D001057:Apolipoproteins E; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D011758:Pyrroles; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C036763:monocyte-macrophage differentiation antigen; C099252:oxidized low density lipoprotein
keywords: angiogenesis inducing agents; antigens, CD36; macrophages; toll-like receptor 2; wound healing