title: Endothelial NO and O₂·⁻ production rates differentially regulate oxidative, nitroxidative, and nitrosative stress in the microcirculation.
abstract: Endothelial dysfunction causes an imbalance in endothelial NO and O₂·⁻ production rates and increased peroxynitrite formation. Peroxynitrite and its decomposition products cause multiple deleterious effects including tyrosine nitration of proteins, superoxide dismutase (SOD) inactivation, and tissue damage. Studies have shown that peroxynitrite formation during endothelial dysfunction is strongly dependent on the NO and O₂·⁻ production rates. Previous experimental and modeling studies examining the role of NO and O₂·⁻ production imbalance on peroxynitrite formation showed different results in biological and synthetic systems. However, there is a lack of quantitative information about the formation and biological relevance of peroxynitrite under oxidative, nitroxidative, and nitrosative stress conditions in the microcirculation. We developed a computational biotransport model to examine the role of endothelial NO and O₂·⁻ production on the complex biochemical NO and O₂·⁻ interactions in the microcirculation. We also modeled the effect of variability in SOD expression and activity during oxidative stress. The results showed that peroxynitrite concentration increased with increase in either O₂·⁻ to NO or NO to O₂·⁻ production rate ratio (QO₂·⁻/QNO or QNO/QO₂·⁻, respectively). The peroxynitrite concentrations were similar for both production rate ratios, indicating that peroxynitrite-related nitroxidative and nitrosative stresses may be similar in endothelial dysfunction or inducible NO synthase (iNOS)-induced NO production. The endothelial peroxynitrite concentration increased with increase in both QO₂·⁻/QNO and QNO/QO₂·⁻ ratios at SOD concentrations of 0.1-100 μM. The absence of SOD may not mitigate the extent of peroxynitrite-mediated toxicity, as we predicted an insignificant increase in peroxynitrite levels beyond QO₂·⁻/QNO and QNO/QO₂·⁻ ratios of 1. The results support the experimental observations of biological systems and show that peroxynitrite formation increases with increase in either NO or O₂·⁻ production, and excess NO production from iNOS or from NO donors during oxidative stress conditions does not reduce the extent of peroxynitrite mediated toxicity.
authors: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, USA. s.kar@wayne.edu
authors: Saptarshi
authors: S
authors: Kar
authors: Mahendra
authors: M
authors: Kavdia
mesh_terms: D003198:Computer Simulation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008833:Microcirculation; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D014443:Tyrosine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D010100:Oxygen
keywords: Biotransport; Computational model; Endothelial dysfunction; Flux; Free radicals; Microcirculation; NO; Peroxynitrite; Production rate; Superoxide; Superoxide dismutase
references: Med Arh. 2005;59(3):156-9
references: 15997672
references: Invest Ophthalmol Vis Sci. 1997 May;38(6):1203-12
references: 9152240
references: Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1530-40
references: 18192221
references: Free Radic Res. 2012 Dec;46(12):1496-513
references: 22998079
references: Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H716-23
references: 16155098
references: Nat Rev Drug Discov. 2007 Aug;6(8):662-80
references: 17667957
references: Microvasc Res. 2010 Dec;80(3):464-76
references: 20888842
references: Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):355-60
references: 11134509
references: Adv Exp Med Biol. 2009;645:7-12
references: 19227443
references: Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H1043-56
references: 14592938
references: Circ Res. 2010 Apr 30;106(8):1319-31
references: 20431074
references: J Biol Chem. 2010 May 7;285(19):14210-6
references: 20194496
references: Hum Exp Toxicol. 2011 Nov;30(11):1828-39
references: 21357632
references: Free Radic Biol Med. 2003 Jun 1;34(11):1488-503
references: 12757859
references: J Biol Chem. 2000 Oct 20;275(42):32467-74
references: 10906338
references: Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37
references: 8944624
references: Prostaglandins Other Lipid Mediat. 2007 Jan;82(1-4):119-27
references: 17164139
references: Pharm Res. 2006 Aug;23(8):1702-11
references: 16850266
references: J Biol Chem. 2000 Feb 4;275(5):3031-6
references: 10652282
references: Microvasc Res. 2009 Jun;78(1):107-18
references: 19285090
references: Braz J Med Biol Res. 2011 Sep;44(9):920-32
references: 21956535
references: Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):106-11
references: 14592844
references: Redox Rep. 2010;15(6):250-8
references: 21208524
references: Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):745-55
references: 22199367
references: Am J Physiol Heart Circ Physiol. 2009 May;296(5):H1466-83
references: 19286953
references: Crit Rev Biomed Eng. 1989;17(3):257-321
references: 2673661
references: J Theor Biol. 2013 Jan 21;317:321-30
references: 23116664
references: Int J Biochem Cell Biol. 2007;39(1):44-84
references: 16978905
references: Infect Immun. 2000 Dec;68(12):6729-36
references: 11083788
references: J Biol Chem. 2000 Mar 3;275(9):6346-52
references: 10692434
references: Circ Res. 1998 Nov 2;83(9):916-22
references: 9797340
references: Thromb Haemost. 2012 Nov;108(5):832-9
references: 23052970
references: Free Radic Biol Med. 2009 Nov 1;47(9):1254-66
references: 19628034
references: Br J Pharmacol. 1999 Jan;126(1):111-20
references: 10051127
references: Am J Physiol. 1949 Nov;159(2):401-8
references: 15393486
references: Exp Biol Med (Maywood). 2012 Jan;237(1):93-8
references: 22156043
references: Am J Physiol Heart Circ Physiol. 2002 Jun;282(6):H2265-77
references: 12003837
references: Free Radic Biol Med. 2000 May 15;28(10):1478-86
references: 10927172
references: J Vasc Surg. 2008 Mar;47(3):599-607
references: 18295111
references: Biochim Biophys Acta. 1999 May 5;1411(2-3):323-33
references: 10320666
references: Cytokine. 1996 Nov;8(11):817-21
references: 9047077
references: Anesth Analg. 2012 Feb;114(2):303-9
references: 22156331
references: Free Radic Biol Med. 2011 Oct 1;51(7):1411-27
references: 21742028
references: Free Radic Biol Med. 2007 May 1;42(9):1359-68
references: 17395009
references: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2528-33
references: 9122229
references: Chem Res Toxicol. 2000 Dec;13(12):1287-93
references: 11123970
references: Circulation. 2006 Apr 4;113(13):1708-14
references: 16585403
references: Biochem J. 2002 Mar 15;362(Pt 3):733-9
references: 11879202
references: News Physiol Sci. 2004 Jun;19:120-3
references: 15143206
references: Circ Res. 2001 Feb 2;88(2):E14-22
references: 11157681
references: Nitric Oxide. 1997;1(6):522-7
references: 9466958
references: Free Radic Biol Med. 2011 Oct 1;51(7):1289-301
references: 21777669
references: Inflammation. 2013 Feb;36(1):242-50
references: 22968433
references: Microvasc Res. 2003 Jul;66(1):49-58
references: 12826074
references: Mol Med. 2002 Oct;8(10):571-80
references: 12477967
references: Am J Pathol. 2003 Dec;163(6):2319-28
references: 14633605
references: J Atheroscler Thromb. 2002;9(4):184-90
references: 12226550
references: Free Radic Biol Med. 2010 Nov 15;49(9):1395-405
references: 20691780
references: Biochem Biophys Res Commun. 1993 Jun 30;193(3):1076-82
references: 8323533
references: Curr Vasc Pharmacol. 2012 Jan;10(1):4-18
references: 22112350
references: Respir Res. 2011 Sep 09;12:119
references: 21906276
references: Curr Pharm Des. 2011 Dec;17(35):3905-32
references: 21933142
references: Diabetes Obes Metab. 2004 Nov;6(6):432-41
references: 15479219
references: J Biol Chem. 2001 Aug 3;276(31):28799-805
references: 11373284
references: J Appl Physiol (1985). 2004 Jul;97(1):293-301
references: 15033959
references: Am J Physiol. 1999 Feb;276(2):C507-10
references: 9950779
references: Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1103-11
references: 16910758
references: FASEB J. 1999 Sep;13(12):1637-46
references: 10463956
references: J Biol Chem. 2000 Oct 20;275(42):32460-6
references: 10906340
references: Cardiovasc Res. 2005 Oct 1;68(1):26-36
references: 16009356
references: Pharmacol Rev. 1991 Jun;43(2):109-42
references: 1852778
references: J Biol Chem. 1996 Jan 5;271(1):40-7
references: 8550595
references: Biochemistry. 1998 Feb 10;37(6):1613-22
references: 9484232
references: Microvasc Res. 2009 Sep;78(2):191-8
references: 19362569
references: Diabetologia. 2012 Jul;55(7):2069-79
references: 22549734
references: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4003-8
references: 15020765
references: Hypertension. 2002 Jun;39(6):1088-94
references: 12052847
references: Nitric Oxide. 1999;3(1):40-54
references: 10355895
references: J Biol Chem. 2001 Apr 13;276(15):11631-8
references: 11152462
references: Am J Physiol Regul Integr Comp Physiol. 2012 Feb 15;302(4):R409-16
references: 22116513
references: Chem Res Toxicol. 2006 Sep;19(9):1160-74
references: 16978020
references: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3404-14
references: 17906108
references: J Appl Physiol (1985). 2003 Jun;94(6):2313-22
references: 12598480
references: Physiol Rev. 2007 Jan;87(1):315-424
references: 17237348
references: Annu Int Conf IEEE Eng Med Biol Soc. 2007;2007:1022-6
references: 18002134
references: Diabetes. 1996 Apr;45(4):471-7
references: 8603769
references: Int J Ophthalmol. 2010;3(4):283-7
references: 22553574
references: Curr Neurovasc Res. 2013 May;10(2):185-94
references: 23469953
references: J Neurosci. 1999 Jul 15;19(14):5910-8
references: 10407030
references: Free Radic Biol Med. 2005 Sep 15;39(6):728-41
references: 16109303
references: PLoS One. 2012;7(6):e38912
references: 22719984
references: Free Radic Biol Med. 2010 Feb 15;48(4):554-9
references: 19969071
references: Am J Physiol Lung Cell Mol Physiol. 2012 Nov 15;303(10):L870-9
references: 22962015
references: Free Radic Biol Med. 2004 Sep 15;37(6):813-22
references: 15304256
references: Ann Biomed Eng. 2010 Feb;38(2):357-70
references: 19847651
references: IEEE Trans Biomed Eng. 1998 Jan;45(1):26-35
references: 9444837