Pulmonary Phosphatidylserine Oxidation in Apoptosis

Summary

Principal Investigator: Valerian Kagan
Affiliation: University of Pittsburgh
Country: USA
Abstract: Although phosphatidylserine (PS) externalization is a well-established early marker of apoptosis and a signal for macrophage-dependent recognition, the functional molecular links between these processes and oxidative stress produced during apoptotic execution are unclear. Our preliminary data suggest a previously unknown signaling role for oxidized PS during Fas-induced apoptosis in Jurkat cells. Since Fas-triggered apoptosis modulates turnover of pulmonary epithelial cells (PUEC) in both healthy and diseased tissue, we propose studying the mechanisms involved in selective PS oxidation and the subsequent PS-dependent signaling events during Fas-mediated apoptosis in PUEC. Our central hypothesis is that PS oxidation is an essential component in the pathway leading to PS externalization during Fas-induced apoptosis in PUEC as well as in efficient recognition and phagocytosis of apoptotic cells by macrophages. As a corollary, inhibition of PS oxidation during Fas-induced apoptosis by antioxidants may affect subsequent externalization/recognition and phagocytosis of apoptotic cells. Our Specific Aims designed to test this hypothesis will: 1) establish a mechanistic link between Fas-induced PS peroxidation and PS-dependent signaling in the PUEC plasma membrane (PS externalization and recognition by macrophages), relationship of PS oxidation to other components of Fas-triggered apoptosis, and extent to which the inhibition of PS oxidation by antioxidants blocks PS-dependent signaling without affecting other major Fas-triggered pathways of apoptosis; 2) establish the catalytic role and mechanisms of cyt c in PS oxidation in plasma membrane; 3) determine the role of PS peroxidation in PS externalization; and 4) reveal the mechanisms for enhanced macrophage recognition and phagocytosis of PUEC expressing oxidized PS. Developmental remodeling of the lung and various acute and chronic lung diseases are characterized by marked apoptosis. Inflammation is limited by effective recognition and phagocytosis of apoptotic cells by macrophages whose critical function is mediated by externalized PS on the surface of apoptotic cells. Our studies will define a new role for site-specific oxidative stress during apoptosis in PUEC, identify oxidized PS as a key signaling molecule that affects macrophage recognition of apoptotic cells and identify antioxidant interventions that can differentially prevent or preserve PS oxidation and downstream signaling events. This will aid in developing new strategies for directed modulation of inflammation in lung disease.
Funding Period: 2002-07-01 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. ncbi An epigrammatic (abridged) recounting of the myriad tales of astonishing deeds and dire consequences pertaining to nitric oxide and reactive oxygen species in mitochondria with an ancillary missive concerning the origins of apoptosis
    Diane E Heck
    Departments of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA
    Toxicology 208:259-71. 2005
  2. ncbi Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesis
    A A Shvedova
    Health Effects Laboratory Div, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
    Am J Physiol Lung Cell Mol Physiol 295:L552-65. 2008
  3. ncbi Mass-spectrometric characterization of phospholipids and their primary peroxidation products in rat cortical neurons during staurosporine-induced apoptosis
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA, USA
    J Neurochem 107:1614-33. 2008
  4. ncbi Molecular design of new inhibitors of peroxidase activity of cytochrome c/cardiolipin complexes: fluorescent oxadiazole-derivatized cardiolipin
    G G Borisenko
    Research Institute of Physico Chemical Medicine, Moscow, Russian Federation
    Biochemistry 47:13699-710. 2008
  5. ncbi Mechanisms of pulmonary toxicity and medical applications of carbon nanotubes: Two faces of Janus?
    A A Shvedova
    Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, United States
    Pharmacol Ther 121:192-204. 2009
  6. ncbi Oxidative stress and inflammatory response in dermal toxicity of single-walled carbon nanotubes
    A R Murray
    Health Effects Laboratory Division, Pathology and Physiology Research Branch, NIOSH, M L 2015, 1095 Willowdale Road, Morgantown, WV 26505, United States
    Toxicology 257:161-71. 2009
  7. ncbi Cytochrome c/cardiolipin relations in mitochondria: a kiss of death
    Valerian E Kagan
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA 15219, USA
    Free Radic Biol Med 46:1439-53. 2009
  8. ncbi Mass-spectrometric analysis of hydroperoxy- and hydroxy-derivatives of cardiolipin and phosphatidylserine in cells and tissues induced by pro-apoptotic and pro-inflammatory stimuli
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219 9361, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 877:2863-72. 2009
  9. ncbi Mitochondria-targeted (2-hydroxyamino-vinyl)-triphenyl-phosphonium releases NO(.) and protects mouse embryonic cells against irradiation-induced apoptosis
    Natalia A Belikova
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    FEBS Lett 583:1945-50. 2009
  10. ncbi Single-walled carbon nanotubes impair human macrophage engulfment of apoptotic cell corpses
    Erika Witasp
    Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
    Inhal Toxicol 21:131-6. 2009

Scientific Experts

  • Anna A Shvedova
  • V E Kagan
  • Ashley R Murray
  • Hulya Bayir
  • Detcho Stoyanovsky
  • D E Heck
  • Vladimir A Tyurin
  • Natalia A Belikova
  • Yulia Y Tyurina
  • Jianfei Jiang
  • Joel S Greenberger
  • Irina I Vlasova
  • Igor V Kurnikov
  • Zhentai Huang
  • Liana V Basova
  • Patrick M Kochanek
  • Qing Zhao
  • Weihong Feng
  • V A Tyurin
  • Andrew A Amoscato
  • Ashley Glumac
  • Muhammad A Tungekar
  • Alexandr Kapralov
  • M Ding
  • Erika Witasp
  • Vladimir B Ritov
  • Alexandra Mnuskin
  • G G Borisenko
  • Bengt Fadeel
  • A A Kapralov
  • Elena R Kisin
  • Jim Peterson
  • Alexandr A Kapralov
  • Anatoly N Osipov
  • B F Serinkan
  • Steven T DeKosky
  • Ronald Hamilton
  • Andriy Lysytsya
  • Bruce Pitt
  • Ruslan Rafikov
  • J Zhao
  • Naveena Yanamala
  • Alejandro K Samhan Arias
  • Joseph Carcillo
  • Mi Yeon Jung
  • Judith Klein-Seetharaman
  • Karen Walson
  • S Leonard
  • B Jiang
  • Michael W Epperly
  • Akihiro Maeda
  • Christian Obinger
  • Grigory Borisenko
  • V Castranova
  • Valentyna Kapralova
  • Paul Georg Furtmüller
  • L Bowman
  • Valentina I Kapralova
  • Y Lu
  • Arlan H Mintz
  • V Vallyathan
  • B Fadeel
  • Karla J Wasserloos
  • RAJESH K ANEJA
  • Vladimir Tyurin
  • E R Kisin
  • A Maeda
  • Xiaojing Zhang
  • Robert S B Clark
  • Jin Ren
  • Minke Tang
  • Vincent Castranova
  • A N Osipov
  • Xiao Chun Shi
  • Andy A Pacheco
  • Xiao-chun Shi
  • Y Y Tyurina
  • Michael J Keane
  • Diane Schwegler Berry
  • L V Basova
  • David H Waldeck
  • N A Belikova
  • Bruce R Pitt
  • Diane Schwegler-Berry
  • Daniel E Winnica
  • Sivaram Arepalli
  • Ala I Potapovich
  • William E Wallace
  • Nagarjun V Konduru
  • Lei Wang

Detail Information

Publications36

  1. ncbi An epigrammatic (abridged) recounting of the myriad tales of astonishing deeds and dire consequences pertaining to nitric oxide and reactive oxygen species in mitochondria with an ancillary missive concerning the origins of apoptosis
    Diane E Heck
    Departments of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA
    Toxicology 208:259-71. 2005
    ....
  2. ncbi Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesis
    A A Shvedova
    Health Effects Laboratory Div, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
    Am J Physiol Lung Cell Mol Physiol 295:L552-65. 2008
    ..SWCNT inhalation was more effective than aspiration in causing inflammatory response, oxidative stress, collagen deposition, and fibrosis as well as mutations of K-ras gene locus in the lung of C57BL/6 mice...
  3. ncbi Mass-spectrometric characterization of phospholipids and their primary peroxidation products in rat cortical neurons during staurosporine-induced apoptosis
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA, USA
    J Neurochem 107:1614-33. 2008
    ..These oxidation products participate in mitochondrial membrane permeability transition and in PtdSer externalization leading to recognition and uptake of apoptotic cells by professional phagocytes...
  4. ncbi Molecular design of new inhibitors of peroxidase activity of cytochrome c/cardiolipin complexes: fluorescent oxadiazole-derivatized cardiolipin
    G G Borisenko
    Research Institute of Physico Chemical Medicine, Moscow, Russian Federation
    Biochemistry 47:13699-710. 2008
    ..We conclude that modified CL combining a nonoxidizable monounsaturated trioleoyl CL with a C(12)-NBD fragment undergoes a regiospecific oxidation thereby representing a novel inhibitor of cyt c peroxidase activity...
  5. ncbi Mechanisms of pulmonary toxicity and medical applications of carbon nanotubes: Two faces of Janus?
    A A Shvedova
    Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, United States
    Pharmacol Ther 121:192-204. 2009
    ....
  6. ncbi Oxidative stress and inflammatory response in dermal toxicity of single-walled carbon nanotubes
    A R Murray
    Health Effects Laboratory Division, Pathology and Physiology Research Branch, NIOSH, M L 2015, 1095 Willowdale Road, Morgantown, WV 26505, United States
    Toxicology 257:161-71. 2009
    ..Altogether, these data indicated that topical exposure to unpurified SWCNT, induced free radical generation, oxidative stress, and inflammation, thus causing dermal toxicity...
  7. ncbi Cytochrome c/cardiolipin relations in mitochondria: a kiss of death
    Valerian E Kagan
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA 15219, USA
    Free Radic Biol Med 46:1439-53. 2009
    ..Finally, new concepts in drug discovery based on the design of mitochondria-targeted inhibitors of cyt c/CL peroxidase and CL peroxidation with antiapoptotic effects are presented...
  8. ncbi Mass-spectrometric analysis of hydroperoxy- and hydroxy-derivatives of cardiolipin and phosphatidylserine in cells and tissues induced by pro-apoptotic and pro-inflammatory stimuli
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219 9361, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 877:2863-72. 2009
    ....
  9. ncbi Mitochondria-targeted (2-hydroxyamino-vinyl)-triphenyl-phosphonium releases NO(.) and protects mouse embryonic cells against irradiation-induced apoptosis
    Natalia A Belikova
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    FEBS Lett 583:1945-50. 2009
    ..We conclude that mitochondria-targeted peroxidase-activatable NO-donors represent a new interesting class of radioprotectors...
  10. ncbi Single-walled carbon nanotubes impair human macrophage engulfment of apoptotic cell corpses
    Erika Witasp
    Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
    Inhal Toxicol 21:131-6. 2009
    ....
  11. ncbi Heterolytic reduction of fatty acid hydroperoxides by cytochrome c/cardiolipin complexes: antioxidant function in mitochondria
    Natalia A Belikova
    Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219 3130, USA
    J Am Chem Soc 131:11288-9. 2009
    ..Regulation of FFA-OOH metabolism may be an important function of cyt c that is associated with elimination of toxic FFA-OOH and synthesis of physiologically active hydroxy-fatty acids in mitochondria...
  12. ncbi Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions
    Valerian E Kagan
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, PA 15219, USA
    Adv Drug Deliv Rev 61:1375-85. 2009
    ..Particular emphasis is placed on the employment of triphenylphosphonium- and hemi-gramicidin S-moieties as two effective vehicles for mitochondrial delivery of antioxidants...
  13. ncbi Peroxidase activity of hemoglobin-haptoglobin complexes: covalent aggregation and oxidative stress in plasma and macrophages
    Alexandr Kapralov
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
    J Biol Chem 284:30395-407. 2009
    ....
  14. ncbi Size-dependent effects of tungsten carbide-cobalt particles on oxygen radical production and activation of cell signaling pathways in murine epidermal cells
    M Ding
    Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
    Toxicol Appl Pharmacol 241:260-8. 2009
    ....
  15. ncbi Mass-spectrometric characterization of phospholipids and their hydroperoxide derivatives in vivo: effects of total body irradiation
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA
    Methods Mol Biol 580:153-83. 2009
    ..The protocols described may be utilized in studies of signaling functions of oxidized phospholipids in cell physiology and pathology...
  16. ncbi Radioprotection by short-term oxidative preconditioning: role of manganese superoxide dismutase
    Natalia A Belikova
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    FEBS Lett 583:3437-42. 2009
    ..Using MnSOD siRNA, we show that MECs with decreased MnSOD levels displayed a lowered ability to preconditioning. Thus oxidative preconditioning may be used for targeted regulation of MnSOD...
  17. ncbi A mitochondria-targeted triphenylphosphonium-conjugated nitroxide functions as a radioprotector/mitigator
    Jianfei Jiang
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15219, USA
    Radiat Res 172:706-17. 2009
    ..We conclude that mitochondrial targeting of TPP-conjugated nitroxides represents a promising approach for the development of novel radioprotectors...
  18. ncbi Increased accumulation of neutrophils and decreased fibrosis in the lung of NADPH oxidase-deficient C57BL/6 mice exposed to carbon nanotubes
    A A Shvedova
    Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, West Virginia University, Morgantown, WV, USA
    Toxicol Appl Pharmacol 231:235-40. 2008
    ..These results demonstrate a role for NADPH oxidase-derived reactive oxygen species in determining course of pulmonary response to SWCNT...
  19. ncbi Cardiolipin deficiency leads to decreased cardiolipin peroxidation and increased resistance of cells to apoptosis
    Zhentai Huang
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    Free Radic Biol Med 44:1935-44. 2008
    ....
  20. ncbi Apoptotic cells quench reactive oxygen and nitrogen species and modulate TNF-alpha/TGF-beta1 balance in activated macrophages: involvement of phosphatidylserine-dependent and -independent pathways
    B F Serinkan
    Cell Death Differ 12:1141-4. 2005
  21. ncbi Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice
    Anna A Shvedova
    Health Effects Laboratory Div, NIOSH, Morgantown, WV, USA
    Am J Physiol Lung Cell Mol Physiol 289:L698-708. 2005
    ..Equal doses of ultrafine carbon black particles or fine crystalline silica (SiO2) did not induce granulomas or alveolar wall thickening and caused a significantly weaker pulmonary inflammation and damage...
  22. ncbi Thioredoxin and lipoic acid catalyze the denitrosation of low molecular weight and protein S-nitrosothiols
    Detcho A Stoyanovsky
    Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    J Am Chem Soc 127:15815-23. 2005
    ..We conclude that both thioredoxin and dihydrolipoic acid may be involved in the regulation of cellular S-nitrosothiols...
  23. ncbi Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors
    Valerian E Kagan
    Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    Nat Chem Biol 1:223-32. 2005
    ..These results provide insight into the role of reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation...
  24. ncbi Direct and indirect effects of single walled carbon nanotubes on RAW 264.7 macrophages: role of iron
    V E Kagan
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, United States
    Toxicol Lett 165:88-100. 2006
    ..Thus, the presence of iron in SWCNT may be important in determining redox-dependent responses of macrophages...
  25. ncbi Nitric oxide inhibits peroxidase activity of cytochrome c.cardiolipin complex and blocks cardiolipin oxidation
    Irina I Vlasova
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15260, USA
    J Biol Chem 281:14554-62. 2006
    ..NO effectively inhibited 1,1'2,2'-tertalinoleoyl cardiolipin oxidation catalyzed by the peroxidase activity of cyt c. Thus, NO can act as a regulator of peroxidase activity of cyt c.CL complexes...
  26. ncbi Peroxidase activity and structural transitions of cytochrome c bound to cardiolipin-containing membranes
    Natalia A Belikova
    Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219-3130, USA
    Biochemistry 45:4998-5009. 2006
    ....
  27. ncbi Mechanisms of cardiolipin oxidation by cytochrome c: relevance to pro- and antiapoptotic functions of etoposide
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, Department of EOH, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219, USA
    Mol Pharmacol 70:706-17. 2006
    ..Thus, oxidation of cardiolipin by the cytochrome c/cardiolipin peroxidase complex, which is essential for apoptosis, is not inhibited by proapoptotic concentrations of the drug...
  28. ncbi Apoptotic interactions of cytochrome c: redox flirting with anionic phospholipids within and outside of mitochondria
    H Bayir
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA 15219, USA
    Biochim Biophys Acta 1757:648-59. 2006
    ..This review is focused on newly discovered redox mechanisms of complexes of cyt c with anionic phospholipids and their role in apoptotic pathways in health and disease...
  29. ncbi The "pro-apoptotic genies" get out of mitochondria: oxidative lipidomics and redox activity of cytochrome c/cardiolipin complexes
    V E Kagan
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219, USA
    Chem Biol Interact 163:15-28. 2006
    ....
  30. ncbi Interactions of cardiolipin and lyso-cardiolipins with cytochrome c and tBid: conflict or assistance in apoptosis
    V A Tyurin
    Cell Death Differ 14:872-5. 2007
  31. ncbi Nitrosative stress inhibits the aminophospholipid translocase resulting in phosphatidylserine externalization and macrophage engulfment: implications for the resolution of inflammation
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, and Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
    J Biol Chem 282:8498-509. 2007
    ..scavenger, DAF-2. Thus, macrophage-induced nitrosylation/oxidation plays an important role in cell clearance, and hence in the resolution of inflammation...
  32. ncbi Cardiolipin switch in mitochondria: shutting off the reduction of cytochrome c and turning on the peroxidase activity
    Liana V Basova
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    Biochemistry 46:3423-34. 2007
    ..Thus, both redox properties and functions of cyt c change upon interaction with CL in the mitochondrial membrane, diminishing cyt c's electron donor/acceptor role and stimulating its peroxidase activity...
  33. ncbi Vitamin E deficiency enhances pulmonary inflammatory response and oxidative stress induced by single-walled carbon nanotubes in C57BL/6 mice
    Anna A Shvedova
    Pathology Physiology Research Branch, HELD, NIOSH, Morgantown, WV, USA
    Toxicol Appl Pharmacol 221:339-48. 2007
    ..Given that pulmonary levels of vitamin E can be manipulated through diet, its effects on SWCNT-induced inflammation may be of practical importance in optimizing protective strategies...
  34. ncbi Single-walled carbon nanotubes: geno- and cytotoxic effects in lung fibroblast V79 cells
    Elena R Kisin
    Pathology Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA
    J Toxicol Environ Health A 70:2071-9. 2007
    ..With two different strains of Salmonella typhimurium, no mutations were found following SWCNT exposure...
  35. ncbi Sequential exposure to carbon nanotubes and bacteria enhances pulmonary inflammation and infectivity
    Anna A Shvedova
    Pathology Physiology Research Branch, HELD, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA
    Am J Respir Cell Mol Biol 38:579-90. 2008
    ..In conclusion, enhanced acute inflammation and pulmonary injury with delayed bacterial clearance after SWCNT exposure may lead to increased susceptibility to lung infection in exposed populations...
  36. ncbi Oxidative lipidomics of apoptosis: quantitative assessment of phospholipid hydroperoxides in cells and tissues
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA
    Methods Mol Biol 610:353-74. 2010
    ..This has important implications for evaluation of apoptosis in vivo. The anionic phospholipids, cardiolipin (CL) and phosphatidylserine (PS), are the preferred peroxidation substrates...