Vascular aging: Chronic oxidative stress and impairment of redox signaling—consequences for vascular homeostasis and disease

References

• Kelly DT. Paul Dudley White International Lecture. Our future society. A global challenge. Circulation. 1997;95:2459–64.
   PubMed Web of Science ®Google Scholar
• Burke GL, Evans GW, Riley WA, Sharrett AR, Howard G, Barnes RW, . Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke. 1995;26:386–91.
   PubMed Web of Science ®Google Scholar
• Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS. Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol. 2005;6:150–66.
   PubMed Web of Science ®Google Scholar
• Cohen RA, Adachi T. Nitric-oxide-induced vasodilatation: regulation by physiologic s-glutathiolation and pathologic oxidation of the sarcoplasmic endoplasmic reticulum calcium ATPase. Trends Cardiovasc Med. 2006;16:109–14.
   PubMed Web of Science ®Google Scholar
• Xu S, Ying J, Jiang B, Guo W, Adachi T, Sharov V, . Detection of sequence-specific tyrosine nitration of manganese SOD and SERCA in cardiovascular disease and aging. Am J Physiol Heart Circ Physiol. 2006;290:H2220–7.
   PubMed Web of Science ®Google Scholar
• Bachschmid M, Schildknecht S, Ullrich V. Redox regulation of vascular prostanoid synthesis by the nitric oxide-superoxide system. Biochem Biophys Res Commun. 2005;338:536–42.
   PubMed Web of Science ®Google Scholar
• Lüscher TF, Vanhoutte PM. The endothelium: modulator of card?ovascular function. Boca Raton, FL, USA:CRC Press; 1991.
   Google Scholar
• Vanhoutte PM. Ageing and endothelial dysfunction. Eur Heart J Supplements. 2002;49:A8–17.
   Google Scholar
• Bachschmid M, Thurau S, Zou MH, Ullrich V. Endothelial cell activation by endotoxin involves superoxide/NO-mediated nitration of prostacyclin synthase and thromboxane receptor stimulation. FASEB J. 2003;17:914–6.
   PubMed Web of Science ®Google Scholar
• Prescott SM, McIntyre TM, Zimmerman GA. Events at the vascular wall: the molecular basis of inflammation. J Investig Med. 2001;49:104–11.
   PubMed Web of Science ®Google Scholar
• van der Loo B, Schildknecht S, Zee R, Bachschmid MM. Signalling processes in endothelial ageing in relation to chronic oxidative stress and their potential therapeutic implications in humans. Exp Physiol. 2009;94:305–10.
   PubMed Web of Science ®Google Scholar
• Bhagat K, Moss R, Collier J, Vallance P. Endothelial “stunning” following a brief exposure to endotoxin: a mechanism to link infection and infarction? Cardiovascular research. 1996;32:822–9.
   PubMed Web of Science ®Google Scholar
• Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet. 1997;349:1391–2.
   PubMed Web of Science ®Google Scholar
• Frein D, Schildknecht S, Bachschmid M, Ullrich V. Redox regulation: a new challenge for pharmacology. Biochem Pharmacol. 2005;70:811–23.
   PubMed Web of Science ®Google Scholar
• Virdis A, Ghiadoni L, Giannarelli C, Taddei S. Endothelial dysfunction and vascular disease in later life. Maturitas. 2010;67:20–4.
   PubMed Web of Science ®Google Scholar
• Gaynor E, Bouvier C, Spaet TH. Vascular lesions: possible pathogenetic basis of the generalized Shwartzman reaction. Science. 1970;170:986–8.
   PubMed Web of Science ®Google Scholar
• Gerhard M, Roddy MA, Creager SJ, Creager MA. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension. 1996;27:849–53.
   PubMed Web of Science ®Google Scholar
• Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE, . Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension. 2003;41:1308–16.
   PubMed Web of Science ®Google Scholar
• Basso N, Paglia N, Stella I, de Cavanagh EM, Ferder L, del Rosario Lores Arnaiz M, . Protective effect of the inhibition of the renin-angiotensin system on aging. Regul Pept. 2005;128:247–52.
   PubMed Web of Science ®Google Scholar
• Oudot A, Martin C, Busseuil D, Vergely C, Demaison L, Rochette L. NADPH oxidases are in part responsible for increased cardiovascular superoxide production during aging. Free Radic Biol Med. 2006;40:2214–22.
   PubMed Web of Science ®Google Scholar
• Gaballa MA, Jacob CT, Raya TE, Liu J, Simon B, Goldman S. Large artery remodeling during aging: biaxial passive and active stiffness. Hypertension. 1998;32:437–43.
   PubMed Web of Science ®Google Scholar
• Zou M, Martin C, Ullrich V. Tyrosine nitration as a mechanism of selective inactivation of prostacyclin synthase by peroxynitrite. Biol Chem. 1997;378:707–13.
   PubMed Web of Science ®Google Scholar
• Viner RI, Ferrington DA, Huhmer AF, Bigelow DJ, Schoneich C. Accumulation of nitrotyrosine on the SERCA2a isoform of SR Ca-ATPase of rat skeletal muscle during aging: a peroxynitrite-mediated process? FEBS Lett. 1996;379:286–90.
   PubMed Web of Science ®Google Scholar
• Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.
   PubMed Web of Science ®Google Scholar
• Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985;43:405–13.
   PubMed Web of Science ®Google Scholar
• Lundblad V, Blackburn EH. An alternative pathway for yeast telomere maintenance rescues est1- senescence. Cell. 1993;73:347–60.
   PubMed Web of Science ®Google Scholar
• Dunham MA, Neumann AA, Fasching CL, Reddel RR. Telomere maintenance by recombination in human cells. Nat Genet. 2000;26:447–50.
   PubMed Web of Science ®Google Scholar
• Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, . Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997;91:25–34.
   PubMed Web of Science ®Google Scholar
• Herrera E, Samper E, Martin-Caballero J, Flores JM, Lee HW, Blasco MA. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 1999;18:2950–60.
   PubMed Web of Science ®Google Scholar
• Lee HW, Blasco MA, Gottlieb GJ, Horner JW 2nd, Greider CW, DePinho RA. Essential role of mouse telomerase in highly proliferative organs. Nature. 1998;392:569–74.
   PubMed Web of Science ®Google Scholar
• Muftuoglu M, Oshima J, von Kobbe C, Cheng WH, Leistritz DF, Bohr VA. The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet. 2008;124:369–77.
   PubMed Web of Science ®Google Scholar
• Mason PJ, Wilson DB, Bessler M. Dyskeratosis congenita—a disease of dysfunctional telomere maintenance. Curr Mol Med. 2005;5:159–70.
   PubMed Web of Science ®Google Scholar
• Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med. 1997; 3:1271–4.
   PubMed Web of Science ®Google Scholar
• Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, . Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279:349–52.
   PubMed Web of Science ®Google Scholar
• Finkel T, Serrano M, Blasco MA. The common biology of cancer and ageing. Nature. 2007;448:767–74.
   PubMed Web of Science ®Google Scholar
• van der Loo B, Fenton MJ, Erusalimsky JD. Cytochemical detection of a senescence-associated beta-galactosidase in endothelial and smooth muscle cells from human and rabbit blood vessels. Exp Cell Res. 1998;241:309–15.
   PubMed Web of Science ®Google Scholar
• Sherr CJ, DePinho RA. Cellular senescence: mitotic clock or culture shock? Cell. 2000;102:407–10.
   PubMed Web of Science ®Google Scholar
• Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88:593–602.
   PubMed Web of Science ®Google Scholar
• Sato I, Morita I, Kaji K, Ikeda M, Nagao M, Murota S. Reduction of nitric oxide producing activity associated with in vitro aging in cultured human umbilical vein endothelial cell. Biochem Biophys Res Commun. 1993;195:1070–6.
   PubMed Web of Science ®Google Scholar
• Nakajima M, Hashimoto M, Wang F, Yamanaga K, Nakamura N, Uchida T, . Aging decreases the production of PGI2 in rat aortic endothelial cells. Exp Gerontol. 1997;3?:685–93.
   Google Scholar
• Erusalimsky JD, Kurz DJ. Cellular senescence in vivo: its relevance in ageing and cardiovascular disease. Exp Gerontol. 2005;40:634–42.
   PubMed Web of Science ®Google Scholar
• Chen J, Goligorsky MS. Premature senescence of endothelial cells: Methusaleh's dilemma. Am J Physiol Heart Circ Physiol. 2006;290:H1729–39.
   PubMed Web of Science ®Google Scholar
• Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, . Age-dependent impairment of angiogenesis. Circulation. 1999;99:111–20.
   PubMed Web of Science ®Google Scholar
• Toussaint O, Medrano EE, von Zglinicki T. Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Exp Gerontol. 2000;35:927–45.
   PubMed Web of Science ®Google Scholar
• Drayton S, Peters G. Immortalisation and transformation revisited. Curr Opin Genet Dev. 2002;12:98–104.
   PubMed Web of Science ®Google Scholar
• Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–9.
   PubMed Web of Science ®Google Scholar
• Colavitti R, Finkel T. Reactive oxygen species as mediators of cellular senescence. IUBMB Life. 2005;57:277–81.
   PubMed Web of Science ®Google Scholar
• Iwasa H, Han J, Ishikawa F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells. 2003;8:131–44.
   PubMed Web of Science ®Google Scholar
• Chen J, Brodsky SV, Goligorsky DM, Hampel DJ, Li H, Gross SS, . Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells. Circ Res. 2002;90:1290–8.
   PubMed Web of Science ®Google Scholar
• Vasa M, Breitschopf K, Zeiher AM, Dimmeler S. Nitric oxide activates telomerase and delays endothelial cell senescence. Circ Res. 2000; 87:540–2.
   PubMed Web of Science ®Google Scholar
• Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, Tsao PS. eNOS activity is reduced in senescent human endothelial cells: Preservation by hTERT immortalization. Circ Res. 2001;89:793–8.
   PubMed Web of Science ®Google Scholar
• Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, . Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res. 2004;94:768–75.
   PubMed Web of Science ®Google Scholar
• Scalera F, Borlak J, Beckmann B, Martens-Lobenhoffer J, Thum T, T ger M, Bode-B ger SM. Endogenous nitric oxide synthesis inhibitor asymmetric dimethyl L-arginine accelerates endothelial cell senescence. Arterioscler Thromb Vasc Biol. 2004;24:1816–22.
   PubMed Web of Science ®Google Scholar
• Nakano-Kurimoto R, Ikeda K, Uraoka M, Nakagawa Y, Yutaka K, Koide M, . Replicative senescence of vascular smooth muscle cells enhances the calcification through initiating the osteoblastic transition. Am J Physiol Heart Circ Physiol. 2009;297:H1673–84.
   PubMed Web of Science ®Google Scholar
• Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298–300.
   PubMedGoogle Scholar
• Harman D. Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci. 2006;1067:10–21.
   PubMed Web of Science ®Google Scholar
• McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969;244:6049–55.
   PubMed Web of Science ®Google Scholar
• Muller FL, Lustgarten MS, Ja?g Y, Richardson A, Van Remmen H. Trends in oxidative aging theories. Free Radic Biol Med. 2007;43:477–503.
   PubMed Web of Science ®Google Scholar
• Radi R. Nitric oxide, oxidants, and protein tyrosine nitration. Proc Natl Acad Sci USA. 2004;101:4003–8.
   PubMed Web of Science ®Google Scholar
• Klumpp G, Schildknecht S, Nastainczyk W, Ullrich V, Bachschmid M. Prostacyclin in the cardiovascular system: new aspects and open questions. Pharmacol Rep. 2005;57 Suppl:120–6.
   Web of Science ®Google Scholar
• Stadtman ER. Protein oxidation and aging. Science. 1992;257:1220–4.
   PubMed Web of Science ®Google Scholar
• Brunk UT, Jones CB, Sohal RS. A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis. Mutat Res. 1992;275:395–403.
   PubMed Web of Science ®Google Scholar
• Sohal RS, Marzabadi MR, Galaris D, Brunk UT. Effect of ambient oxygen concentration on lipofuscin accumulation in cultured rat heart myocytes—a novel in vitro model of lipofuscinogenesis. Free Radic Biol Med. 1989;6:23–30.
   PubMed Web of Science ®Google Scholar
• Gil P, Farinas F, Casado A, Lopez-Fernandez E. Malondialdehyde: a possible marker of ageing. Gerontology. 2002;48:209–14.
   PubMed Web of Science ®Google Scholar
• Grune T, Jung T, Merker K, Davies KJ. Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease. Int J Biochem Cell Biol. 2004;36:2519–30.
   PubMed Web of Science ®Google Scholar
• Barja G, Herrero A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J. 2000;14:312–8.
   PubMed Web of Science ®Google Scholar
• Wenzel P, Schuhmacher S, Kienhofer J, Muller J, Hortmann M, Oelze M, . Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction. Cardiovasc Res. 2008;80:280–9.
   PubMed Web of Science ®Google Scholar
• Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, . Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005;308:1909–11.
   PubMed Web of Science ®Google Scholar
• Landis GN, Tower J. Superoxide dismutase evolution and life span regulation. Mech Ageing Dev. 2005;126:365–79.
   PubMed Web of Science ®Google Scholar
• Ladiges W, Van Remmen H, Strong R, Ikeno Y, Treuting P, Rabinovitch P, . Lifespan extension in genetically modified mice. Aging Cell. 2009;8:346–52.
   PubMed Web of Science ®Google Scholar
• Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972;20:145–7.
   PubMed Web of Science ®Google Scholar
• Hartman P, Ponder R, Lo HH, Ishii N. Mitochondrial oxidative stress can lead to nuclear hypermutability. Mech Ageing Dev. 2004;125:417–20.
   PubMed Web of Science ®Google Scholar
• Miwa S, Brand MD. The topology of superoxide production by complex III and glycerol 3-phosphate dehydrogenase in Drosophila mitochondria. Biochim Biophys Acta. 2005;1709:214–9.
   PubMed Web of Science ®Google Scholar
• Lambert AJ, Brand MD. Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. Biochem J. 2004;382:511–7.
   PubMed Web of Science ®Google Scholar
• Jacobs HT, Lehtinen SK, Spelbrink JN. No sex please, we're mitochondria: a hypothesis on the somatic unit of inheritance of mammalian mtDNA. Bioessays. 2000;22:564–72.
   PubMed Web of Science ®Google Scholar
• O’Rourke B. Pathophysiological and protective roles of mitochondrial ion channels. J Physiol. 2000;529 Pt 1:23–36.
   PubMed Web of Science ®Google Scholar
• Romashko DN, Marban E, O’Rourke B. Subcellular metabolic transients and mitochondrial redox waves in heart cells. Proc Natl Acad Sci USA. 1998;95:1618–23.
   PubMed Web of Science ®Google Scholar
• Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, . The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta. 1998;1366:177–96.
   PubMed Web of Science ®Google Scholar
• Ichas F, Jouaville LS, Mazat JP. Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell. 1997;89:1145–53.
   PubMed Web of Science ®Google Scholar
• Duchen MR, Leyssens A, Crompton M. Transient mitochondrial depolarizations reflect focal sarcoplasmic reticular calcium release in single rat cardiomyocytes. J Cell Biol. 1998;142:975–88.
   PubMed Web of Science ®Google Scholar
• Riva A, Tandler B, Lesnefsky EJ, Conti G, Loffredo F, Vazquez E, . Structure of cristae in cardiac mitochondria of aged rat. Mech Ageing Dev. 2006;127:917–21.
   PubMed Web of Science ®Google Scholar
• Palmer JW, Tandler B, Hoppel CL. Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem. 1977;252:8731–9.
   PubMed Web of Science ®Google Scholar
• Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA. 2006;103:2653–8.
   PubMed Web of Science ®Google Scholar
• Castro L, Rodriguez M, Radi R. Aconitase is readily inactivated by peroxynitrite, but not by its precursor, nitric oxide. J Biol Chem. 1994; 269:29409–15.
   PubMed Web of Science ®Google Scholar
• Radi R, Rodriguez M, Castro L, Telleri R. Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys. 1994; 308:89–95.
   PubMed Web of Science ®Google Scholar
• Stachowiak O, Dolder M, Wallimann T, Richter C. Mitochondrial creatine kinase is a prime target of peroxynitrite-induced modification and inactivation. J Biol Chem. 1998;273:16694–9.
   PubMed Web of Science ®Google Scholar
• Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet. 1992;2:324–9.
   PubMed Web of Science ®Google Scholar
• Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA. 1988; 85:6465–7.
   PubMed Web of Science ®Google Scholar
• Burwell LS, Nadtochiy SM, Tompkins AJ, Young S, Brookes PS. Direct evidence for S-nitrosation of mitochondrial complex I. Biochem J. 2006;394:627–34.
   PubMed Web of Science ®Google Scholar
• Melov S, Schneider JA, Day BJ, Hinerfeld D, Coskun P, Mirra SS, . A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase. Nat Genet. 1998;18:159–63.
   PubMed Web of Science ®Google Scholar
• Ohashi M, Runge MS, Faraci FM, Heistad DD.?MnSOD deficiency increases endothelial dysfunction in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2006;26:2331–6.
   PubMed Web of Science ®Google Scholar
• Brown KA, Didion SP, Andresen JJ, Faraci FM. Effect of aging, MnSOD deficiency, and genetic background on endothelial function: evidence for MnSOD haploinsufficiency. Arterioscler Thromb Vasc Biol. 2007; 27:1941–6.
   PubMed Web of Science ®Google Scholar
• Strassburger M, Bloch W, Sulyok S, Schuller J, Keist AF, Schmidt A, . Heterozygous deficiency of manganese superoxide dismutase results in severe lipid peroxidation and spontaneous apoptosis in murine myocardium in vivo. Free Radic Biol Med. 2005;38:1458–70.
   PubMed Web of Science ®Google Scholar
• Kokoszka JE, Coskun P, Esposito LA, Wallace DC. Increased mitochondrial oxidative stress in the Sod2 (+ /-) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis. Proc Natl Acad Sci USA. 2001;98:2278–83.
   PubMed Web of Science ®Google Scholar
• Wei YH. Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med. 1998;217:53–63.
   PubMed Web of Science ®Google Scholar
• Larsen NB, Rasmussen M, Rasmussen LJ. Nuclear and mitochondrial DNA repair: similar pathways? Mitochondrion. 2005;5:89–108.
   PubMed Web of Science ®Google Scholar
• van der Loo B, Lüscher TF. Endothelium-mediated signaling and vascular aging. In: Hagen, T, editor. Mechanisms of cardiovascular aging. Advances in Cell Aging and Gerontology. Vol. 11. Amsterdam: Elsevier Science; 2002. p. 127–44.
   Google Scholar
• Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–47.
   PubMed Web of Science ®Google Scholar
• Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120:483–95.
   PubMed Web of Science ®Google Scholar
• Corral-Debrinski M, Shoffner JM, Lott MT, Wallace DC. Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res. 1992;275:169–80.
   PubMed Web of Science ®Google Scholar
• Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, . Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429:417–23.
   PubMed Web of Science ®Google Scholar
• Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, . Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005;309:481–4.
   PubMed Web of Science ®Google Scholar
• Lewis W, Day BJ, Kohler JJ, Hosseini SH, Chan SS, Green EC, . Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma. Lab Invest. 2007;87:326–35.
   PubMed Web of Science ®Google Scholar
• Ballinger SW, Patterson C, Knight-Lozano CA, Burow DL, Conklin CA, Hu Z, . Mitochondrial integrity and function in atherogenesis. Circulation. 2002;106:544–9.
   PubMed Web of Science ®Google Scholar
• Gutierrez J, Ballinger SW, Darley-Usmar VM, Landar A. Free radicals, mitochondria, and oxidized lipids: the emerging role in signal transduction in vascular cells. Circ Res. 2006;99:924–32.
   PubMed Web of Science ®Google Scholar
• Bonawitz ND, Shadel GS. Rethinking the mitochondrial theory of aging: the role of mitochondrial gene expression in lifespan determination. Cell Cycle. 2007;6:1574–8.
   PubMed Web of Science ®Google Scholar
• Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, . Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011;470:359–65.
   PubMed Web of Science ®Google Scholar
• Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–6.
   PubMed Web of Science ®Google Scholar
• Korbut R, Trabka-Janik E, Gryglewski RJ. Cytoprotection of human polymorphonuclear leukocytes by stimulators of adenylate and guanylate cyclases. Eur J Pharmacol. 1989;165:171–2.
   PubMed Web of Science ®Google Scholar
• Radomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987;2:1057–8.
   PubMed Web of Science ®Google Scholar
• Marks DS, Vita JA, Folts JD, Keaney JF Jr, Welch GN, Loscalzo J. Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide. J Clin Invest. 1995;96:2630–8.
   PubMed Web of Science ®Google Scholar
• Periasamy M, Kalyanasundaram A. SERCA pump isoforms: their role in calcium transport and disease. Muscle Nerve. 2007;35:430–42.
   PubMed Web of Science ®Google Scholar
• Pfitzer G. Invited review: regulation of myosin phosphorylation in smooth muscle. J Appl Physiol. 2001;91:497–503.
   PubMed Web of Science ®Google Scholar
• Loirand G, Guilluy C, Pacaud P. Regulation of Rho proteins by phosphorylation in the cardiovascular system. Trends Cardiovasc Med. 2006;16:199–204.
   PubMed Web of Science ®Google Scholar
• Stuehr DJ, Santolini J, Wang ZQ, Wei CC, Adak S. Update on mechanism and catalytic regulation in the NO synthases. J Biol Chem. 2004;279:36167–70.
   PubMed Web of Science ®Google Scholar
• Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res. 2005;66:286–94.
   PubMed Web of Science ®Google Scholar
• Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006;113:1708–14.
   PubMed Web of Science ®Google Scholar
• Raman CS, Martasek P, Masters BSS. Structural themes determining function in nitric oxide synthases. San Diego:Academic Press; 2000.
   Google Scholar
• Dashwood MR, Crump A, Shi-Wen X, Loesch A. Identification of neuronal nitric oxide synthase (nNOS) in human penis: a potential role of reduced neuronally-derived nitric oxide in erectile dysfunction. Curr Pharm Biotechnol. 2011 Apr 20. [Epub ahead of print]
   PubMed Web of Science ®Google Scholar
• Wink DA, Miranda KM, Espey MG, Pluta RM, Hewett SJ, Colton C, . Mechanisms of the antioxidant effects of nitric oxide. Antioxid Redox Signal. 2001;3:203–13.
   PubMed Web of Science ®Google Scholar
• Hummel SG, Fischer AJ, Martin SM, Schafer FQ, Buettner GR. Nitric oxide as a cellular antioxidant: a little goes a long way. Free Radic Biol Med. 2006;40:501–6.
   PubMed Web of Science ®Google Scholar
• Wink DA, Cook JA, Kim SY, Vodovotz Y, Pacelli R, Krishna MC, . Superoxide modulates the oxidation and nitrosation of thiols by nitric oxide-derived reactive intermediates. Chemical aspects involved in the balance between oxidative and nitrosative stress. J Biol Chem. 1997; 272:11147–51.
   PubMed Web of Science ®Google Scholar
• Schildknecht S, Bachschmid M, Ullrich V. Peroxynitrite provides the peroxide tone for PGHS-2-dependent prostacyclin synthesis in vascular smooth muscle cells. FASEB J. 2005;19:1169–71.
   PubMed Web of Science ®Google Scholar
• Schildknecht S, van der Loo B, Weber K, Tiefenthaler K, Daiber A, Bachschmid MM. Endogenous peroxynitrite modulates PGHS-1- dependent thromboxane A2 formation and aggregation in human platelets. Free Radic Biol Med. 2008;45:512–20.
   PubMed Web of Science ®Google Scholar
• Hogg N, Struck A, Goss SP, Santanam N, Joseph J, Parthasarathy S, . Inhibition of macrophage-dependent low density lipoprotein oxidation by nitric-oxide donors. J Lipid Res. 1995;36:1756–62.
   PubMed Web of Science ®Google Scholar
• Hogg N, Kalyanaraman B, Joseph J, Struck A, Parthasarathy S. Inhibition of low-density lipoprotein oxidation by nitric oxide. Potential role in atherogenesis. FEBS Lett. 1993;334:170–4.
   PubMed Web of Science ®Google Scholar
• Knapp LT, Klann E. Superoxide-induced stimulation of protein kinase C via thiol modification and modulation of zinc content. J Biol Chem. 2000;275:24136–45.
   PubMed Web of Science ®Google Scholar
• Ullrich V, Namgaladze D, Frein D. Superoxide as inhibitor of calcineurin and mediator of redox regulation. Toxicol Lett. 2003;139:107–10.
   PubMed Web of Science ®Google Scholar
• Gardner PR, Raineri I, Epstein LB, White CW. Superoxide radical and iron modulate aconitase activity in mammalian cells. J Biol Chem. 1995;270:13399–405.
   PubMed Web of Science ®Google Scholar
• Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK. Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2004;24:677–83.
   PubMed Web of Science ®Google Scholar
• Adler A, Messina E, Sherman B, Wang Z, Huang H, Linke A, . NAD(P)H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats. Am J Physiol Heart Circ Physiol. 2003;285:H1015–22.
   PubMed Web of Science ®Google Scholar
• Krause KH. Aging: a revisited theory based on free radicals generated by NOX family NADPH oxidases. Exp Gerontol. 2007;42:256–62.
   PubMed Web of Science ®Google Scholar
• Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, . Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003; 111:1201–9.
   PubMed Web of Science ®Google Scholar
• Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest. 2002;109:817–26.
   PubMed Web of Science ®Google Scholar
• Fleming I, Mohamed A, Galle J, Turchanowa L, Brandes RP, Fisslthaler B, . Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKCalpha. Cardiovasc Res. 2005;65:897–906.
   PubMed Web of Science ®Google Scholar
• Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, . Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res. 2002;90:E58–65.
   PubMed Web of Science ®Google Scholar
• Chen CA, Wang TY, Varadharaj S, Reyes LA, Hemann C, Talukder MA, . S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature. 2010;468:1115–8.
   PubMed Web of Science ®Google Scholar
• Zou MH, Cohen R, Ullrich V. Peroxynitrite and vascular endothelial dysfunction in diabetes mellitus. Endothelium. 2004;11:89–97.
   PubMed Web of Science ®Google Scholar
• Hink U, Li H, Mo?lnau H, Oelze M, Matheis E, Hartmann M, . Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001;88:E14–22.
   PubMed Web of Science ®Google Scholar
• Alderman M, Aiyer KJ. Uric acid: role in cardiovascular disease and effects of losartan. Curr Med Res Opin. 2004;20:369–79.
   PubMed Web of Science ®Google Scholar
• Massie HR, Shumway ME, Whitney SJ. Uric acid content of Drosophila decreases with aging. Exp Gerontol. 1991;26:609–14.
   PubMed Web of Science ®Google Scholar
• Zeldin DC. Epoxygenase pathways of arachidonic acid metabolism. J Biol Chem. 2001;276:36059–62.
   PubMed Web of Science ®Google Scholar
• Fleming I, Michaelis UR, Bredenkotter D, Fisslthaler B, Dehghani F, Brandes RP, . Endothelium-derived hyperpolarizing factor synthase (Cytochrome P450 2C9) is a functionally significant source of reactive oxygen species in coronary arteries. Circ Res. 2001;88:44–51.
   PubMed Web of Science ®Google Scholar
• Wenzel P, Mollnau H, Oelze M, Schulz E, Wickramanayake JM, Muller J, . First evidence for a crosstalk between mitochondrial and NADPH oxidase-derived reactive oxygen species in nitroglycerin-triggered vascular dysfunction. Antioxid Redox Signal. 2008;10:1435–47.
   PubMed Web of Science ®Google Scholar
• Daiber A. Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim Biophys Acta. 2010;1797:897–906.
   PubMed Web of Science ®Google Scholar
• Wosniak J Jr, Santos CX, Kowaltowski AJ, Laurindo FR. Cross-talk between mitochondria and NADPH oxidase: effects of mild mitochondrial dysfunction on angiotensin II-mediated increase in Nox isoform expression and activity in vascular smooth muscle cells. Antioxid Redox Signal. 2009;11:1265–78.
   PubMed Web of Science ®Google Scholar
• Lee SB, Bae IH, Bae YS, Um HD. Link between mitochondria and NADPH oxidase 1 isozyme for the sustained production of reactive oxygen species and cell death. J biol chem. 2006;281:36228–35.
   PubMed Web of Science ®Google Scholar
• Burwell LS, Brookes PS. Mitochondria as a target for the cardioprotective effects of nitric oxide in ischemia-reperfusion injury. Antioxid Redox Signal. 2008;10:579–99.
   PubMed Web of Science ®Google Scholar
• Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA. 1990;87:1620–4.
   PubMed Web of Science ®Google Scholar
• Daiber A, Schildknecht S, Muller J, Kamuf J, Bachschmid MM, Ullrich V. Chemical model systems for cellular nitros(yl)ation reactions. Free Radic Biol Med. 2009;47:458–67.
   PubMed Web of Science ®Google Scholar
• Jourd'heuil D, Lancaster JR Jr, Fukuto J, Roberts DD, Miranda KM, Mayer B, . The bell-shaped curve for peroxynitrite-mediated oxidation and nitration of NO/O2-* is alive and well. J Biol Chem. 2010;285:le15; author reply le16.
   PubMed Web of Science ®Google Scholar
• Bosworth CA, Toledo JC Jr, Zmijewski JW, Li Q, Lancaster JR Jr. Dinitrosyliron complexes and the mechanism(s) of cellular protein nitrosothiol formation from nitric oxide. Proc Natl Acad Sci USA. 2009;106:4671–6.
   PubMed Web of Science ®Google Scholar
• Pimentel D, Haeussler DJ, Matsui R, Burgoyne J, Cohen RA, Bachschmid M. Regulation of cell physiology and pathology by protein S-glutathionylation. Lessons learned from the cardiovascular system. Antioxid Redox Signal. 2011 Oct 19. [Epub ahead of print] PubMed PMID: 22010840.
   Web of Science ®Google Scholar
• Mohr S, Stamler JS, Brune B. Mechanism of covalent m?dification of glyceraldehyde-3-phosphate dehydrogenase at its active site thiol by nitric oxide, peroxynitrite and related nitrosating agents. FEBS Lett. 1994;348:223–7.
   PubMed Web of Science ®Google Scholar
• Lee JH, Yang ES, Park JW. Inactivation of NADP + -dependent isocitrate dehydrogenase by peroxynitrite. Implications for cytotoxicity and alcohol-induced liver injury. J Biol Chem. 2003;278:51360–71.
   PubMed Web of Science ®Google Scholar
• Kim PK, Kwon YG, Chung HT, Kim YM. Regulation of caspases by nitric oxide. Ann N Y Acad Sci. 2002;962:42–52.
   PubMed Web of Science ®Google Scholar
• Chung HT, Pae HO, Choi BM, Billiar TR, Kim YM. Nitric oxide as a bioregulator of apoptosis. Biochem Biophys Res Commun. 2001;282:1075–9.
   PubMed Web of Science ®Google Scholar
• Clementi E, Brown GC, Feelisch M, Moncada S. Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proc Natl Acad Sci USA. 1998;95:7631–6.
   PubMed Web of Science ®Google Scholar
• Moon KH, Kim BJ, Song BJ. Inhibition of mitochondrial aldehyde dehydrogenase by nitric oxide-mediated S-nitrosylation. FEBS Lett. 2005;579:6115–20.
   PubMed Web of Science ®Google Scholar
• Sydow K, Daiber A, Oelze M, Chen Z, August M, Wendt M, . Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance. J Clin Invest. 2004;113:482–9.
   PubMed Web of Science ®Google Scholar
• Zou MH, Bachschmid M. Hypoxia-reoxygenation triggers coronary vasospasm in isolated bovine coronary arteries via tyrosine nitration of prostacyclin synthase. J Exp Med. 1999;190:135–9.
   PubMed Web of Science ®Google Scholar
• Kozak AJ, Liu F, Funovics P, Jacoby A, Kubant R, Malinski T. Role of peroxynitrite in the process of vascular tone regulation by nitric oxide and prostanoids—a nanotechnological approach. Prostaglandins Leukot Essent Fatty Acids. 2005;72:105–13.
   PubMed Web of Science ®Google Scholar
• Zou MH, Ullrich V. Peroxynitrite formed by simultaneous generation of nitric oxide and superoxide selectively inhibits bovine aortic prostacyclin synthase. FEBS Lett. 1996;382:101–4.
   PubMed Web of Science ®Google Scholar
• Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, . Role of prostacyclin in the cardiovascular response to thromboxane A2. Science. 2002;296:539–41.
   PubMed Web of Science ®Google Scholar
• Francois H, Athirakul K, Howell D, Dash R, Mao L, Kim HS, . Prostacyclin protects against elevated blood pressure and cardiac fibrosis. Cell Metab. 2005;2:201–7.
   PubMed Web of Science ®Google Scholar
• Gryglewski RJ, Dembinska-Kiec A, Korbut R. A possible role of thromboxane A2 (TXA2) and prostacyclin (PGI2) in circulation. Acta Biol Med Ger. 1978;37:715–23.
   PubMedGoogle Scholar
• Espey MG, Thomas DD, Miranda KM, Wink DA. Focusing of nitric oxide mediated nitrosation and oxidative nitrosylation as a consequence of reaction with superoxide. Proc Natl Acad Sci USA. 2002;99:11127–32.
   PubMed Web of Science ®Google Scholar
• Im JW, Kim HK, Kim ND, Choi JS, Yu BP, Yang HS, . Activation of cyclooxygenases by H2O2 and t-butylhydroperoxide in aged rat lung. Biotechnol Lett. 2004;26:1665–9.
   PubMed Web of Science ®Google Scholar
• Seiler A, Schneider M, Forster H, Roth S, Wirth EK, Culmsee C, . Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lip?xygenase dependent- and AIF-mediated cell death. Cell Metab. 2008;8:237–48.
   PubMed Web of Science ®Google Scholar
• van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, . Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000;192:1731–44.
   PubMed Web of Science ®Google Scholar
• Hamilton CA, Brosnan MJ, McIntyre M, Graham D, Dominiczak AF. Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. Hypertension. 2001;37:529–34.
   PubMed Web of Science ®Google Scholar
• Yoon HJ, Cho SW, Ahn BW, Yang SY. Alterations in the activity and expression of endothelial NO synthase in aged human endothelial cells. Mech Ageing Dev. 2010;131:119–23.
   PubMed Web of Science ®Google Scholar
• Wenzel P, Schulz E, Oelze M, Muller J, Schuhmacher S, Alhamdani MS, . AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats. Free Radic Biol Med. 2008;45:619–26.
   PubMed Web of Science ®Google Scholar
• Bachschmid M, van der Loo B, Schuler K, Labugger R, Thurau S, Eto M, . Oxidative stress-associated vascular aging is independent of the protein kinase C/NAD(P)H oxidase pathway. Arch Gerontol Geriatr. 2004;38:181–90.
   PubMed Web of Science ®Google Scholar
• Breusing N, Arndt J, Voss P, Bresgen N, Wiswedel I, Gardemann A, . Inverse correlation of protein oxidation and proteasome activity in liver and lung. Mech Ageing Dev. 2009;130:748–53.
   PubMed Web of Science ®Google Scholar
• Breusing N, Grune T. Regulation of proteasome-mediated protein degradation during oxidative stress and aging. Biol Chem. 2008;389:203–9.
   PubMed Web of Science ®Google Scholar
• Merker K, Ullrich O, Schmidt H, Sitte N, Grune T. Stability of the nuclear protein turnover during cellular senescence of human fibroblasts. FASEB J. 2003;17:1963–5.
   PubMed Web of Science ®Google Scholar
• Li M, Chiu JF, Kelsen A, Lu SC, Fukagawa NK. Identification and characterization of an Nrf2-mediated ARE upstream of the rat glutamate cysteine ligase catalytic subunit gene (GCLC). J Cell Biochem. 2009; 107:944–54.
   PubMed Web of Science ®Google Scholar
• Stewart KG, Zhang Y, Davidge ST. Aging increases PGHS-2-dependent vasoconstriction in rat mesenteric arteries. Hypertension. 2000;35:1242–7.
   PubMed Web of Science ®Google Scholar
• Shi Y, Man RY, Vanhoutte PM. Two isoforms of cyclooxygenase contribute to augmented endothelium-dependent contractions in femoral arteries of 1-year-old rats. Acta Pharmacol Sin. 2008;29:185–92.
   PubMed Web of Science ®Google Scholar
• Rolland PH, Jouve R, Pellegrin E, Mercier C, Serradimigni A. Alteration in prostacyclin and prostaglandin E2 production. Correlation with changes in human aortic atherosclerotic disease. Arteriosclerosis. 1984;4:70–8.
   PubMedGoogle Scholar
• Beharka AA, Wu D, Serafini M, Meydani SN. Mechanism of vitamin E inhibition of cyclooxygenase activity in macrophages from old mice: role of peroxynitrite. Free Radic Biol Med. 2002;32:503–11.
   PubMed Web of Science ®Google Scholar
• Goodwin JS, Messner RP. Sensitivity of lymphocytes to prostaglandin E2 increases in subjects over age 70. J Clin Invest. 1979;64:434–9.
   PubMed Web of Science ®Google Scholar
• Hailer NP, Oppermann E, Leckel K, Cinatl J, Markus BH, Blaheta RA. Prostaglandin E2 induces expression of P-selectin (CD62P) on cultured human umbilical vein endothelial cells and enhances endothelial binding of CD4-T-cells. Transplantation. 20?0;70:236–40.
   PubMed Web of Science ®Google Scholar
• Yang HH, Kim C, Jung B, Kim KS, Kim JR. Involvement of IGF binding protein 5 in prostaglandin E(2)-induced cellular senescence in human fibroblasts. Biogerontology. 2011;12:239–52.
   PubMed Web of Science ®Google Scholar
• Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging. Circulation. 2003;107(3):490–7. Review. PubMed PMID: 12551876.
   PubMed Web of Science ®Google Scholar
• Landar A, Zmijewski JW, Dickinson DA, Le Goffe C, Johnson MS, Milne GL, . Interaction of electrophilic lipid oxidation products with mitochondria in endothelial cells and formation of reactive oxygen species. Am J Physiol Heart Circ Physiol. 2006;290:H1777–87.
   PubMed Web of Science ®Google Scholar
• Levonen AL, Landar A, Ramachandran A, Ceaser EK, Dickinson DA, Zanoni G, . Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Biochem J. 2004;378:373–82.
   PubMed Web of Science ®Google Scholar
• Luo C, Urgard E, Vooder T, Metspalu A. The role of COX-2 and Nrf2/ARE in anti-inflammation and antioxidative stress: Aging and anti-aging. Med Hypotheses. 2011;77:174–8.
   PubMed Web of Science ®Google Scholar
• McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD. Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox- insensitive Neh6 degron. J Biol Chem. 2004;279:31556–67.
   PubMed Web of Science ®Google Scholar
• Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, Monticone RE, . Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta. J Gerontol A Biol Sci Med Sci. 2011;66:866–75.
   PubMed Web of Science ®Google Scholar
• Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G, . Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol. 2011;301:H363–72.
   PubMed Web of Science ®Google Scholar
• Cernuda-Morollon E, Pineda-Molina E, Canada FJ, Perez-Sala D. 15-Deoxy-delta 12,14-prostaglandin J2 inhibition of NF-kappaB-DNA binding through covalent modification of the p50 subunit. J Biol Chem. 2001;276:35530–6.
   PubMed Web of Science ®Google Scholar
• Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M, . Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature. 2000;403:103–8.
   PubMed Web of Science ®Google Scholar
• Kasjanovova D, Adameckova D, Gratzlova J, Hegyi L. Sex-related and age-related differences in platelet function in vitro: influence of hematocrit. Mech Ageing Dev. 1993;71:103–9.
   PubMed Web of Science ®Google Scholar
• Genova ML, Pich MM, Bernacchia A, Bianchi C, Biondi A, Bovina C, . The mitochondrial production of reactive oxygen species in relation to aging and pathology. Ann N Y Acad Sci. 2004;1011:86–100.
   PubMed Web of Science ®Google Scholar
• Wachowicz B, Olas B, Zbikowska HM, Buczynski A. Generation of reactive oxygen species in blood platelets. Platelets. 2002;13:175–82.
   PubMed Web of Science ®Google Scholar
• Kim JW, Zou Y, Yoon S, Lee JH, Kim YK, Yu BP, . Vascular aging: molecular modulation of the prostanoid cascade by calorie restriction. J Gerontol A Biol Sci Med Sci. 2004;59:B876–85.
   PubMed Web of Science ®Google Scholar
• van der Loo B, Labugger R, Aebischer CP, Skepper JN, Bachschmid M, Spitzer V, . Cardiovascular aging is associated with vitamin E increase. Circulation. 2002;105:1635–8.
   PubMed Web of Science ®Google Scholar
• Koga T, Kwan P, Zubik L, Ameho C, Smith D, Meydani M. Vitamin E supplementation suppresses macrophage accumulation and endothelial cell expression of adhesion molecules in the aorta of hypercholesterolemic rabbits. Atherosclerosis. 2004;176:265–72.
   PubMed Web of Science ®Google Scholar
• Liu L, Meydani M. Combined vitamin C and E supplementation retards early progression of arteriosclerosis in heart transplant patients. Nutr Rev. 2002;60:368–71.
   PubMed Web of Science ®Google Scholar
• Park SK, Page GP, Kim K, Allison DB, Meydani M, Weindruch R, . alpha- and gamma-Tocopherol prevent age-related transcriptional alterations in the heart and brain of mice. J Nutr. 2008;138:1010–8.
   PubMed Web of Science ®Google Scholar
• Stralin P, Karlsson K, Johansson BO, Marklund SL. The interstitium of the human arterial wall contains very large amounts of extracellular superoxide dismutase. Arterioscler Thromb Vasc Biol. 1995;15:2032–6.
   PubMed Web of Science ®Google Scholar
• van der Loo B, Bachschmid M, Skepper JN, Labugger R, Schildknecht S, Hahn R, . Age-associated cellular relocation of Sod 1 as a self-defense is a futile mechanism to prevent vascular aging. Biochem Biophys Res Commun. 2006;344:972–80.
   PubMed Web of Science ®Google Scholar
• Wenzel P, Schuhmacher S, Kienh fer J, M ller J, Hortmann M, Oelze M, Schulz E, Treiber N, Kawamoto T, Scharffetter-Kochanek K, M nzel T, B rkle A, Bachschmid MM, Daiber A. Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction. Cardiovasc Res. 2008;80:280–9. Epub 2008 Jul 2. PubMed PMID: 18596060.
   PubMed Web of Science ®Google Scholar
• Didion SP, Kinzenbaw DA, Schrader LI, Faraci FM. Heterozygous CuZn superoxide dismutase deficiency produces a vascular phenotype with aging. Hypertension. 2006;48:1072–9.
   PubMed Web of Science ®Google Scholar
• Yang YM, Huang A, Kaley G, Sun D. eNOS uncoupling and endothelial dysfunction in aged vessels. Am J Physiol Heart Circ Physiol. 2009; 297:H1829–36.
   PubMed Web of Science ®Google Scholar
• Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, . Extension of life-span with superoxide dismutase/catalase mimetics. Science. 2000;289:1567–9.
   PubMed Web of Science ®Google Scholar
• Radovits T, Seres L, Gero D, Lin LN, Beller CJ, Chen SH, . The peroxynitrite decomposition catalyst FP15 improves ageing-associated cardiac and vascular dysfunction. Mech Ageing Dev. 2007;128:173–81.
   PubMed Web of Science ®Google Scholar
• Brown KA, Chu Y, Lund DD, Heistad DD, Faraci FM. Gene transfer of extracellular superoxide dismutase protects against vascular dysfunction with aging. Am J Physiol Heart Circ Physiol. 2006;290:H2600–5.
   PubMed Web of Science ®Google Scholar
• Csiszar A, Labinskyy N, Zhao X, Hu F, Serpillon S, Huang Z, . Vascular superoxide and hydrogen peroxide production and oxidative stress resistance in two closely related rodent species with disparate longevity. Aging Cell. 2007;6:783–97.
   PubMed Web of Science ®Google Scholar
• Mitsui A, Hamuro J, Nakamura H, Kondo N, Hirabayashi Y, Ishizaki-Koizumi S, . Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. Antioxid Redox Signal. 2002;4:693–6.
   PubMed Web of Science ®Google Scholar
• Yang X, Doser TA, Fang CX, Nunn JM, Janardhanan R, Zhu M, . Metallothionein prolongs survival and antagonizes senescence- associated cardiomyocyte diastolic dysfunction: role of oxidative stress. FASEB J. 2006;20:1024–6.
   PubMed Web of Science ®Google Scholar
• Fang CX, Doser TA, Yang X, Sreejayan N, Ren J. Metallothionein antagonizes aging-induced cardiac contractile dysfunction: role of PTP1B, insulin receptor tyrosine phosphorylation and Akt. Aging Cell. 2006;5:177–85.
   PubMed Web of Science ®Google Scholar
• Yan LJ, Levine RL, Sohal RS. Oxidative damage during aging targets mitochondrial aconitase. Proc Natl Acad Sci USA. 1997;94:11168–72.
   PubMed Web of Science ®Google Scholar
• Harris N, Costa V, MacLean M, Mollapour M, Moradas-Ferreira P, Piper PW. Mnsod overexpression extends the yeast chronological (G(0)) life span but acts independently of Sir2p histone deacetylase to shorten the replicative life span of dividing cells. Free Radic Biol Med. 2003;34:1599–606.
   PubMed Web of Science ®Google Scholar
• Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, . Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation. 2009;119:2789–97.
   PubMed Web of Science ®Google Scholar
• Ren J, Li Q, Wu S, Li SY, Babcock SA. Cardiac overexpression of antioxidant catalase attenuates aging-induced cardiomyocyte relaxation dysfunction. Mech Ageing Dev. 2007;128:276–85.
   PubMed Web of Science ®Google Scholar
• Schafer E, Seelert H, Reifschneider NH, Krause F, Dencher NA, Vonck J. Architecture of active mammalian respiratory chain supercomplexes. J Biol Chem. 2006;281:15370–5.
   PubMed Web of Science ®Google Scholar
• Wang Y, Bogenhagen DF. Human mitochondrial DNA nucleoids are linked to protein folding machinery and metabolic enzymes at the mitochondrial inner membrane. J Biol Chem. 2006;281:25791–802.
   PubMed Web of Science ®Google Scholar
• Kim SC, Sprung R, Chen Y, Xu Y, Ball H, Pei J, . Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell. 2006;23:607–18.
   PubMed Web of Science ®Google Scholar
• Chen Y, Zhang J, Lin Y, Lei Q, Guan KL, Zhao S, . Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Rep. 2011;12:534–41.
   PubMed Web of Science ®Google Scholar
• Kienhofer J, Haussler DJ, Ruckelshausen F, Muessig E, Weber K, Pimentel D, . Association of mitochondrial antioxidant enzymes with mitochondrial DNA as integral nucleoid constituents. FASEB J. 2009; 23:2034–44.
   PubMed Web of Science ®Google Scholar
• Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De Rango F, . A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics. 2005; 85:258–63.
   PubMed Web of Science ®Google Scholar
• Kowald A, Kirkwood TB. Accumulation of defective mitochondria through delayed degradation of damaged organelles and its possible role in the ageing of post-mitotic and dividing cells. J Theor Biol. 2000;202:145–60.
   PubMed Web of Science ®Google Scholar
• Twig G, Shirihai OS. The interplay between mitochondrial dynamics and mitophagy. Antioxid Redox Signal. 2011;14:1939–51.
   PubMed Web of Science ®Google Scholar
• Lugus JJ, Ngoh GA, Bachschmid MM, Walsh K. Mitofusins are required for angiogenic function and modulate different signaling pathways in cultured endothelial cells. J Mol Cell Cardiol. 2011;51:885–93.
   PubMed Web of Science ®Google Scholar
• Masoro EJ. Caloric restriction-induced life extension of rats and mice: a critique of proposed me?hanisms. Biochim Biophys Acta. 2009; 1790:1040–8.
   PubMed Web of Science ®Google Scholar
• Baur JA, Chen D, Chini EN, Chua K, Cohen HY, de Cabo R, . Dietary restriction: standing up for sirtuins. Science. 2010;329:1012–3; author reply 13–14.
   PubMed Web of Science ®Google Scholar
• Johnson FB, Sinclair DA, Guarente L. Molecular biology of aging. Cell. 1999;96:291–302.
   PubMed Web of Science ®Google Scholar
• Palacios JA, Herranz D, De Bonis ML, Velasco S, Serrano M, Blasco MA. SIRT1 contributes to telomere maintenance and augments global homologous recombination. J Cell Biol. 2010;191:1299–313.
   PubMed Web of Science ®Google Scholar
• Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, . Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–42.
   PubMed Web of Science ®Google Scholar
• Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5:493–506.
   PubMed Web of Science ®Google Scholar
• Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, . SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem. 2010;285:8340–51.
   PubMed Web of Science ®Google Scholar
• Xu S, Jiang B, Hou X, Shi C, Bachschmid MM, Zang M, . High-fat diet increases and the polyphenol, S17834, decreases acetylation of the sirtuin-1-dependent lysine-382 on p53 and apoptotic signaling in atherosclerotic lesion-prone aortic endothelium of normal mice. J Cardiovasc Pharmacol. 2011;58:263–71.
   PubMed Web of Science ®Google Scholar
• Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, . SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 2007;21:2644–58.
   PubMed Web of Science ®Google Scholar
• Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, . SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 2007;104:14855–60.
   PubMed Web of Science ®Google Scholar
• Potente M, Dimmeler S. NO targets SIRT1: a novel signaling network in endothelial senescence. Arterioscler Thromb Vasc Biol. 2008;28:1577–9.
   PubMed Web of Science ®Google Scholar
• Ungvari Z, Labinskyy N, Mukhopadhyay P, Pinto JT, Bagi Z, Ballabh P, . Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am J Physiol Heart Circ Physiol. 2009;297:H1876–81.
   PubMed Web of Science ®Google Scholar
• Csiszar A, Labinskyy N, Pinto JT, Ballabh P, Zhang H, Losonczy G, . Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. 2009;297:H13–20.
   PubMed Web of Science ®Google Scholar
• Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, . Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol. 2010;299:H18–24.
   PubMed Web of Science ®Google Scholar
• Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, . Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010;143:802–12.
   PubMed Web of Science ®Google Scholar
• Zhong L, Mostoslavsky R. Fine tuning our cellular factories: sirtuins in mitochondrial biology. Cell Metab. 2011;13:621–6.
   PubMed Web of Science ®Google Scholar
• Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78:547–81.
   PubMed Web of Science ®Google Scholar
• Grollman AP, Moriya M. Mutagenesis by 8-oxoguanine: an enemy within. Trends Genet. 1993;9:246–9.
   PubMed Web of Science ®Google Scholar
• Schodel J, Padmapriya P, Marx A, Huang PL, Ertl G, Kuhlencordt PJ. Expression of neuronal nitric oxide synthase splice variants in atherosclerotic plaques of apoE knockout mice. Atherosclerosis. 2009;206:383–9.
   PubMed Web of Science ®Google Scholar
• Schwarz PM, Kleinert H, Forstermann U. Potential functional significance of brain-type and muscle-type nitric oxide synthase I expressed in adventitia and media of rat aorta. Arterioscler Thromb Vasc Biol. 1999;19:2584–90.
   PubMed Web of Science ®Google Scholar
• Fleming I, Busse R. Signal transduction of eNOS activation. Cardiovasc Res. 1999;43:532–41.
   PubMed Web of Science ®Google Scholar
• Nohl H, Staniek K, Sobhian B, Bahrami S, Redl H, Kozlov AV. Mitochondria recycle nitrite back to the bioregulator nitric monoxide. Acta Biochim Pol. 2000;47:913–21.
   PubMed Web of Science ®Google Scholar
• Maia LB, Moura JJ. Nitrite reduction by xanthine oxidase family enzymes: a new class of nitrite reductases. J Biol Inorg Chem. 2011;16:443–60.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Naughton DP, Blake DR, Benjamin N, Stevens CR, Winyard PG, . Human xanthine oxidase converts nitrite ions into nitric oxide (NO). Biochem Soc Trans. 1997;25:524S.
   PubMedGoogle Scholar
• Lundberg JO, Gladwin MT, Ahluwalia A, Benjamin N, Bryan NS, Butler A, . Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol. 2009;5:865–9.
   PubMed Web of Science ®Google Scholar
• van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim-Shapiro DB, . Nitrite as regulator of hypoxic signaling in mammalian physiology. Med Res Rev. 2009;29:683–741.
   PubMed Web of Science ®Google Scholar
• Chen CA, Druhan LJ, Varadharaj S, Chen YR, Zweier JL. Phosphorylation of endothelial nitric-oxide synthase regulates superoxide generation from the enzyme. J Biol Chem. 2008;283:27038–47. Epub 2008 Jul 13. PubMed PMID: 18622039; PubMed Central PMCID: PMC2556006.
   PubMed Web of Science ®Google Scholar
• Song Y, Cardounel AJ, Zweier JL, Xia Y. Inhibition of superoxide generation from neuronal nitric oxide synthase by heat shock protein 90: implications in NOS regulation. Biochemistry. 2002;41:10616–22.
   PubMed Web of Science ®Google Scholar
• Brandes RP, Schroder K. Differential vascular functions of Nox family NADPH oxidases. Curr Opin Lipidol. 2008;19:513–8.
   PubMed Web of Science ®Google Scholar
• Lassegue B, Griendling KK. NADPH oxidases: functions and pathologies in the vasculature. Arteriosclerosis, thrombosis, and vascular biology. 2010;30:653–61.
   PubMed Web of Science ®Google Scholar
• Herkert O, Djordjevic T, BelAiba RS, Gorlach A. Insights into the redox control of blood coagulation: role of vascular NADPH oxidase-derived reactive oxygen species in the thrombogenic cycle. Antioxid Redox Signal. 2004;6:765–76.
   PubMed Web of Science ®Google Scholar
• George J, Struthers AD. Role of urate, xanthine oxidase and the effects of allopurinol in vascular oxidative stress. Vasc Health Risk Manag. 2009;5:265–72.
   PubMedGoogle Scholar