Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

THE HAZENLABORATORYRESEARCH ASSOCIATESMichael Greenberg, Ph.D.Marie-Luise Brennan, Ph.D.Renliang Zhang, M.D., Ph.D.RESEARCH FELLOWSRon Aviles, M.D.Waddah Maskoun, M.D.Mehdi Shishehbor, D.O.POSTDOCTORAL FELLOWSNagella Nukuna, Ph.D.Lian Shan, Ph.D.LEAD TECHNICIANDave SchmittTECHNICIANSXiaoming Fu, M.S.Shirley MannSteven MaximukDragos MihaitaMeghan SmithSTUDENTSPaula FintonCheryl MolendaLaura NarineWei SongCOLLABORATORSGuy Chisolm, Ph.D. 1Raed Dweik, M.D. 2Stephen Ellis, M.D. 3Serpil Erzurum, M.D. 2Gary Francis, M.D. 3Paul Fox, Ph.D. 1Mani Kavuru, M.D. 2Michael Lauer, M.D. 3Patrick McCarthy, M.D. 4Steven Nissen, M.D. 3Marc Penn, M.D.,Ph.D. 1,3Eugene Podrez, M.D., Ph.D. 1Robert G. Salomon, Ph.D. 5Dennis Stuehr, Ph.D. 6James Thomas, M.D. 3Eric Topol, M.D. 3Jay Yadav, M.D. 3James Young, M.D. 31Dept. of Cell Biology, CCF2Dept. of Pulmonary andCritical Care Medicine, CCF3Dept. of CardiovascularMedicine, CCF4Dept. of Thoracic andCardiovascular Surgery, CCF5Dept. of Chemistry, CaseWestern Reserve Univ.,Cleveland, OH6Dept. of Immunology, CCFThe overall goals of my laboratory are tounderstand the mechanisms throughwhich phagocytic cells promote protein,lipid and DNA oxidative damage as part of theirnormal function and in chronic inflammatorydiseases. Three major research programscurrently focus on the role of oxidative damagein the pathogenesis of disease. We employ amultidisciplinary approach, combining clinical,animal model, cellular and molecular biologicalstudies with those that rely heavily on chemicaland analytical methods (e.g., mass spectrometry,nuclear magnetic resonance, high-performanceliquid chromatography, and electron paramagneticresonance).Myeloperoxidase, Oxidant Stress andAtherogenesisAtherosclerosis is a chronic inflammatoryprocess in which oxidative damage within theartery wall is implicated in the pathogenesis ofthe disease. Mononuclearphagocytes,an inflammatory cellcapable of generatinga variety of oxidizingspecies, are earlycomponents ofarterial lesions.Myeloperoxidase(MPO) is anabundant hemeprotein secreted fromactivated phagocytesand is present inhuman atheroscleroticlesions. Wehave shown thatMPO is one pathwayfor protein andThe Department of Cell BiologyFree Radicals and Reactive OxidantsCause Inflammatory Injury in DiseaseStanley Hazen, M.D., Ph.D.lipoprotein oxidation in vivo. Multiple distinctproducts of MPO are enriched in humanatherosclerotic lesions and low-density lipoproteins(LDLs) recovered from human atheroma.In recent clinical studies we demonstrated thatMPO levels serve as an independent predictor ofcardiovascular risk. Current research efforts areaimed at examining the mechanisms of howMPO participates in atherogenesis through use ofgenetic, biochemical, analytical, cell biologicaland clinical studies.Eosinophil Peroxidase and AsthmaEosinophils play an essential role in vivo,destroying pathogenic microorganisms, parasitesand tumor cells. To perform these functions,they have evolved enzymatic mechanisms togenerate an arsenal of reactive oxidant species;however, their potent oxidants also have greatpotential to harm healthy tissue. Oxidativeproducts of eosinophil activation are implicatedin the genesis of tissue injury inasthma. Eosinophil peroxidase(EPO), an abundant hemeprotein secreted duringeosinophil activation, usesH 2O 2to generate potentcytotoxic oxidants.We have identifiedseveral pathways for EPOdependentoxidative damage ofcellular proteins and lipids thatmight contribute to the originsof cellular injury in theinflammatory response inasthma. The potential roles ofthese pathways in human andmurine models of asthma arebeing examined.Brennan, M.L., Wu, W., Fu, X., Shen, Z., Song, W., Frost, H., Vadseth, C., Narine, L., Lenkiewicz, E.,Borchers, M.T., Lusis, A.J., Lee, J.J., Lee, N.A., Abu-Soud, H.M., Ischiropoulos, H., and S.L. Hazen (2002)A tale of two controversies: defining both the role of peroxidases in nitrotyrosine formation in vivo usingeosinophil peroxidase and myeloperoxidase-deficient mice, and the nature of peroxidase-generatedreactive nitrogen species. J. Biol. Chem. 277:17415-17427.Podrez, E.A., Poliakov, E., Shen, Z., Zhang, R., Deng, Y., Sun, M., Finton, P.J., Shan, L., Gugiu, B., Fox,P.L., Hoff, H.F., Salomon, R.G., and S.L. Hazen (2002) Identification of a novel family of oxidizedphospholipids that serve as ligands for the macrophage scavenger receptor CD36. J. Biol. Chem.277:38503-38516.Podrez, E.A., Poliakov, E., Shen, Z., Zhang, R., Deng, Y., Sun, M., Finton, P.J., Shan, L., Febbraio, M.,Hajjar, D.P., Silverstein, R.L., Hoff, H.F., Salomon, R.G., and S.L. Hazen (2002) A novel family ofatherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptorCD36 and is enriched in atherosclerotic lesions. J. Biol. Chem. 277:38517-38523.Hazen, S.L., and G.M. Chisolm (2002) Oxidized phosphatidylcholines: Pattern recognition ligands formultiple pathways of the innate immune response. Proc. Natl. Acad. Sci. USA 99:12515-12517.Zhang, R., Brennan, M.L., Shen, Z., MacPherson, J.C., Schmitt, D., Molenda, C.E., and S.L. Hazen (2002)Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites ofinflammation. J. Biol. Chem. 277:46116-46122.74