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Genomes and Genes | Pulmonary Phosphatidylserine Oxidation in ApoptosisSummaryPrincipal 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
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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 apoptosisDiane E Heck
Departments of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA
Toxicology 208:259-71. 2005....
Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesisA 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...- Mass-spectrometric characterization of phospholipids and their primary peroxidation products in rat cortical neurons during staurosporine-induced apoptosisVladimir 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... - Molecular design of new inhibitors of peroxidase activity of cytochrome c/cardiolipin complexes: fluorescent oxadiazole-derivatized cardiolipinG 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... 
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....- Oxidative stress and inflammatory response in dermal toxicity of single-walled carbon nanotubesA 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... - Cytochrome c/cardiolipin relations in mitochondria: a kiss of deathValerian 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... - Mass-spectrometric analysis of hydroperoxy- and hydroxy-derivatives of cardiolipin and phosphatidylserine in cells and tissues induced by pro-apoptotic and pro-inflammatory stimuliVladimir 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.... - Mitochondria-targeted (2-hydroxyamino-vinyl)-triphenyl-phosphonium releases NO(.) and protects mouse embryonic cells against irradiation-induced apoptosisNatalia 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... - Single-walled carbon nanotubes impair human macrophage engulfment of apoptotic cell corpsesErika Witasp
Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Inhal Toxicol 21:131-6. 2009.... - Heterolytic reduction of fatty acid hydroperoxides by cytochrome c/cardiolipin complexes: antioxidant function in mitochondriaNatalia 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... - Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactionsValerian 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... - Peroxidase activity of hemoglobin-haptoglobin complexes: covalent aggregation and oxidative stress in plasma and macrophagesAlexandr Kapralov
Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
J Biol Chem 284:30395-407. 2009.... - Size-dependent effects of tungsten carbide-cobalt particles on oxygen radical production and activation of cell signaling pathways in murine epidermal cellsM 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.... - Mass-spectrometric characterization of phospholipids and their hydroperoxide derivatives in vivo: effects of total body irradiationYulia 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... - Radioprotection by short-term oxidative preconditioning: role of manganese superoxide dismutaseNatalia 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... - A mitochondria-targeted triphenylphosphonium-conjugated nitroxide functions as a radioprotector/mitigatorJianfei 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... - Increased accumulation of neutrophils and decreased fibrosis in the lung of NADPH oxidase-deficient C57BL/6 mice exposed to carbon nanotubesA 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... - Cardiolipin deficiency leads to decreased cardiolipin peroxidation and increased resistance of cells to apoptosisZhentai 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.... - Apoptotic cells quench reactive oxygen and nitrogen species and modulate TNF-alpha/TGF-beta1 balance in activated macrophages: involvement of phosphatidylserine-dependent and -independent pathwaysB F Serinkan
Cell Death Differ 12:1141-4. 2005 - Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in miceAnna 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... - Thioredoxin and lipoic acid catalyze the denitrosation of low molecular weight and protein S-nitrosothiolsDetcho 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... - Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factorsValerian 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... - Direct and indirect effects of single walled carbon nanotubes on RAW 264.7 macrophages: role of ironV 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... - Nitric oxide inhibits peroxidase activity of cytochrome c.cardiolipin complex and blocks cardiolipin oxidationIrina 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... - Peroxidase activity and structural transitions of cytochrome c bound to cardiolipin-containing membranesNatalia 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.... - Mechanisms of cardiolipin oxidation by cytochrome c: relevance to pro- and antiapoptotic functions of etoposideYulia 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... - Apoptotic interactions of cytochrome c: redox flirting with anionic phospholipids within and outside of mitochondriaH 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... - The "pro-apoptotic genies" get out of mitochondria: oxidative lipidomics and redox activity of cytochrome c/cardiolipin complexesV 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.... - Interactions of cardiolipin and lyso-cardiolipins with cytochrome c and tBid: conflict or assistance in apoptosisV A Tyurin
Cell Death Differ 14:872-5. 2007 - Nitrosative stress inhibits the aminophospholipid translocase resulting in phosphatidylserine externalization and macrophage engulfment: implications for the resolution of inflammationYulia 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... - Cardiolipin switch in mitochondria: shutting off the reduction of cytochrome c and turning on the peroxidase activityLiana 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... - Vitamin E deficiency enhances pulmonary inflammatory response and oxidative stress induced by single-walled carbon nanotubes in C57BL/6 miceAnna 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... - Single-walled carbon nanotubes: geno- and cytotoxic effects in lung fibroblast V79 cellsElena 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... - Sequential exposure to carbon nanotubes and bacteria enhances pulmonary inflammation and infectivityAnna 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... - Oxidative lipidomics of apoptosis: quantitative assessment of phospholipid hydroperoxides in cells and tissuesVladimir 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...