title: Regulation of reactive oxygen species by p53: implications for nitric oxide-mediated apoptosis.
abstract: Nitric oxide (NO) induces vascular smooth muscle cell (VSMC) apoptosis in part through activation of p53. Traditionally, p53 has been thought of as the gatekeeper, determining if a cell should undergo arrest and repair or apoptosis following exposure to DNA-damaging agents, depending on the severity of the damage. However, our laboratory previously demonstrated that NO induces apoptosis to a much greater extent in p53(-/-) compared with p53(+/+) VSMC. Increased reactive oxygen species (ROS) within VSMC has been shown to induce VSMC apoptosis, and recently it was found that the absence of, or lack of, functional p53 leads to increased ROS and oxidative stress within different cell types. This study investigated the differences in intracellular ROS levels between p53(-/-) and p53(+/+) VSMC and examined if these differences were responsible for the increased susceptibility to NO-induced apoptosis observed in p53(-/-) VSMC. We found that p53 actually protects VSMC from NO-induced apoptosis by increasing antioxidant protein expression [i.e., peroxiredoxin-3 (PRx-3)], thereby reducing ROS levels and cellular oxidative stress. We also observed that the NO-induced apoptosis in p53(-/-) VSMC was largely abrogated by pretreatment with catalase. Furthermore, when the antioxidant protein PRx-3 and its specific electron acceptor thioredoxin-2 were silenced within p53(+/+) VSMC with small-interfering RNA, not only did these cells exhibit greater ROS production, but they also exhibited increased NO-induced apoptosis similar to that observed in p53(-/-) VSMC. These findings suggest that ROS mediate NO-induced VSMC apoptosis and that p53 protects VSMC from NO-induced apoptosis by decreasing intracellular ROS. This research demonstrates that p53 has antioxidant functions in stressed cells and also suggests that p53 has antiapoptotic properties.
authors.affiliation: Division of Vascular Surgery, Northwestern Univ., 676 N. St. Clair, no. 650, Chicago, IL 60611, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Popowich
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Vavra
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Walsh
authors.forename: Hussein A
authors.initials: HA
authors.lastname: Bhikhapurwala
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Rossi
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.forename: Oliver O
authors.initials: OO
authors.lastname: Aalami
authors.forename: Melina R
authors.initials: MR
authors.lastname: Kibbe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D005979:Glutathione Peroxidase / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2
chemical_list: D005979:Glutathione Peroxidase; D018398:Homeodomain Proteins; D009569:Nitric Oxide; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D013879:Thioredoxins; D016159:Tumor Suppressor Protein p53; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2; C484663:Shox2 protein, mouse; C515559:Txn1 protein, mouse; C516112:Txn2 protein, mouse; C000722068:Gpx1 protein, mouse
references.citation: Mol Cancer Ther. 2008 Mar;7(3):510-20
references.pmid: 18347138
references.citation: Circ Res. 1995 Feb;76(2):305-9
references.pmid: 7834842
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10364-9
references.pmid: 12136132
references.citation: J Biol Chem. 2004 Oct 1;279(40):41975-84
references.pmid: 15280382
references.citation: Annu Rev Med. 1997;48:489-509
references.pmid: 9046979
references.citation: Surgery. 1997 Aug;122(2):255-63
references.pmid: 9288130
references.citation: Methods Cell Sci. 2001;23(4):185-8
references.pmid: 12486328
references.citation: Am J Physiol Cell Physiol. 2002 Mar;282(3):C625-34
references.pmid: 11832348
references.citation: J Cardiovasc Pharmacol. 1995 Apr;25(4):674-8
references.pmid: 7596138
references.citation: J Biochem Mol Biol. 2002 Jan 31;35(1):116-26
references.pmid: 16248976
references.citation: Free Radic Biol Med. 2008 Jan 1;44(1):73-81
references.pmid: 18045549
references.citation: Nat Rev Mol Cell Biol. 2002 Mar;3(3):214-20
references.pmid: 11994742
references.citation: J Clin Invest. 1989 May;83(5):1774-7
references.pmid: 2540223
references.citation: Free Radic Biol Med. 2002 Dec 1;33(11):1440-50
references.pmid: 12446201
references.citation: Circulation. 1997 Nov 18;96(10):3602-9
references.pmid: 9396461
references.citation: J Clin Invest. 1994 Nov;94(5):2036-44
references.pmid: 7525653
references.citation: FEBS Lett. 2001 Oct 5;506(2):135-9
references.pmid: 11591387
references.citation: Biochem Soc Trans. 2006 Nov;34(Pt 5):953-6
references.pmid: 17052235
references.citation: Circulation. 2000 Apr 25;101(16):1982-9
references.pmid: 10779466
references.citation: Biochem Biophys Res Commun. 2001 Apr 20;282(5):1075-9
references.pmid: 11302723
references.citation: J Vasc Surg. 2008 Jan;47(1):173-82
references.pmid: 18178471
references.citation: BMB Rep. 2008 Feb 29;41(2):164-9
references.pmid: 18315954
references.citation: Subcell Biochem. 2007;44:295-315
references.pmid: 18084900
references.citation: Mol Cancer Res. 2003 Jul;1(9):682-9
references.pmid: 12861054
references.citation: Biochem Biophys Res Commun. 1987 Nov 13;148(3):1482-9
references.pmid: 2825688
references.citation: J Cell Biol. 2006 Oct 23;175(2):225-35
references.pmid: 17060495
references.citation: J Leukoc Biol. 2001 Jul;70(1):87-95
references.pmid: 11435490
references.citation: J Vasc Surg. 2007 Jun;45 Suppl A:A64-73
references.pmid: 17544026
references.citation: Nature. 1997 Sep 18;389(6648):300-5
references.pmid: 9305847
references.citation: Circulation. 1998 Sep 22;98(12):1212-8
references.pmid: 9743513
references.citation: Antioxid Redox Signal. 2005 Mar-Apr;7(3-4):432-5
references.pmid: 15706090
references.citation: FASEB J. 2001 Nov;15(13):2518-20
references.pmid: 11641266
references.citation: FEBS Lett. 1997 Mar 10;404(2-3):249-52
references.pmid: 9119073
references.citation: Antioxid Redox Signal. 2002 Oct;4(5):845-54
references.pmid: 12470513
references.citation: Antioxid Redox Signal. 2005 Mar-Apr;7(3-4):497-507
references.pmid: 15706097
references.citation: N Engl J Med. 1993 Dec 30;329(27):2002-12
references.pmid: 7504210
references.citation: Nat Med. 2005 Dec;11(12):1306-13
references.pmid: 16286925
references.citation: Vascular. 2007 Nov-Dec;15(6):324-35
references.pmid: 18053416
references.citation: Cancer Res. 2004 May 1;64(9):3022-9
references.pmid: 15126337
references.citation: Cell Death Differ. 2003 Aug;10(8):864-9
references.pmid: 12867993
references.citation: Circulation. 1997 Feb 4;95(3):553-4
references.pmid: 9024134
references.citation: Curr Pharm Des. 2006;12(34):4445-68
references.pmid: 17168753
references.citation: Circ Res. 2005 Apr 1;96(6):667-74
references.pmid: 15746445
references.citation: Vascul Pharmacol. 2006 Nov;45(5):268-76
references.pmid: 17052961
references.citation: J Biol Chem. 2002 Apr 5;277(14):12343-50
references.pmid: 11805088
references.citation: Biochim Biophys Acta. 2001 Mar 1;1504(1):46-57
references.pmid: 11239484