Dynamic Regulation of Metabolism and Respiration by Endogenously Produced Nitric Oxide Protects Against Oxidative Stress

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2001 Sep 20

PMID 11562476

Citations 21

Authors

E Paxinou

M Weisse

Q Chen

J M Souza

C Hertkorn

M Selak

E Daikhin

M Yudkoff

G Sowa

W C Sessa

H Ischiropoulos

Affiliations

Soon will be listed here.

Abstract

One of the many biological functions of nitric oxide is the ability to protect cells from oxidative stress. To investigate the potential contribution of low steady state levels of nitric oxide generated by endothelial nitric oxide synthase (eNOS) and the mechanisms of protection against H(2)O(2), spontaneously transformed human ECV304 cells, which normally do not express eNOS, were stably transfected with a green fluorescent-tagged eNOS cDNA. The eNOS-transfected cells were found to be resistant to injury and delayed death following a 2-h exposure to H(2)O(2) (50-150 microM). Inhibition of nitric oxide synthesis abolished the protective effect against H(2)O(2) exposure. The ability of nitric oxide to protect cells depended on the presence of respiring mitochondria as ECV304+eNOS cells with diminished mitochondria respiration (rho(-)) are injured to the same extent as nontransfected ECV304 cells and recovery of mitochondrial respiration restores the ability of nitric oxide to protect against H(2)O(2)-induced death. Nitric oxide also found to have a profound effect in cell metabolism, because ECV304+eNOS cells had lower steady state levels of ATP and higher utilization of glucose via the glycolytic pathway than ECV304 cells. However, the protective effect of nitric oxide against H(2)O(2) exposure is not reproduced in ECV304 cells after treatment with azide and oligomycin suggesting that the dynamic regulation of respiration by nitric oxide represent a critical and unrecognized primary line of defense against oxidative stress.

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References

Lawrie A, Rizzuto R, Pozzan T, Simpson A . A role for calcium influx in the regulation of mitochondrial calcium in endothelial cells. J Biol Chem. 1996; 271(18):10753-9. DOI: 10.1074/jbc.271.18.10753. View

Shen W, Hintze T, Wolin M . Nitric oxide. An important signaling mechanism between vascular endothelium and parenchymal cells in the regulation of oxygen consumption. Circulation. 1995; 92(12):3505-12. DOI: 10.1161/01.cir.92.12.3505. View

Chang J, Rao N, Markewitz B, Hoidal J, Michael J . Nitric oxide donor prevents hydrogen peroxide-mediated endothelial cell injury. Am J Physiol. 1996; 270(6 Pt 1):L931-40. DOI: 10.1152/ajplung.1996.270.6.L931. View

Abedi H, Zachary I . Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem. 1997; 272(24):15442-51. DOI: 10.1074/jbc.272.24.15442. View

Ma Z, Landt M, Bohrer A, Ramanadham S, KIPNIS D, Turk J . Interleukin-1 reduces the glycolytic utilization of glucose by pancreatic islets and reduces glucokinase mRNA content and protein synthesis by a nitric oxide-dependent mechanism. J Biol Chem. 1997; 272(28):17827-35. DOI: 10.1074/jbc.272.28.17827. View

Balakirev MYu , Khramtsov V, Zimmer G . Modulation of the mitochondrial permeability transition by nitric oxide. Eur J Biochem. 1997; 246(3):710-8. DOI: 10.1111/j.1432-1033.1997.00710.x. View

Bowie A, Moynagh P, ONeill L . Lipid peroxidation is involved in the activation of NF-kappaB by tumor necrosis factor but not interleukin-1 in the human endothelial cell line ECV304. Lack of involvement of H2O2 in NF-kappaB activation by either cytokine in both primary and.... J Biol Chem. 1997; 272(41):25941-50. DOI: 10.1074/jbc.272.41.25941. View

Hermann C, Zeiher A, Dimmeler S . Shear stress inhibits H2O2-induced apoptosis of human endothelial cells by modulation of the glutathione redox cycle and nitric oxide synthase. Arterioscler Thromb Vasc Biol. 1998; 17(12):3588-92. DOI: 10.1161/01.atv.17.12.3588. View

Gonzalez-Zulueta M, Ensz L, Mukhina G, Lebovitz R, Zwacka R, Engelhardt J . Manganese superoxide dismutase protects nNOS neurons from NMDA and nitric oxide-mediated neurotoxicity. J Neurosci. 1998; 18(6):2040-55. PMC: 6792928. View

10.

Giulivi C, Poderoso J, Boveris A . Production of nitric oxide by mitochondria. J Biol Chem. 1998; 273(18):11038-43. DOI: 10.1074/jbc.273.18.11038. View

11.

Andrieu-Abadie N, Caspar-Bauguil S, BROSSMER R, Levade T, Negre-Salvayre A, Salvayre R . Apoptosis and activation of the sphingomyelin-ceramide pathway induced by oxidized low density lipoproteins are not causally related in ECV-304 endothelial cells. J Biol Chem. 1998; 273(42):27389-95. DOI: 10.1074/jbc.273.42.27389. View

12.

Souza J, Radi R . Glyceraldehyde-3-phosphate dehydrogenase inactivation by peroxynitrite. Arch Biochem Biophys. 1998; 360(2):187-94. DOI: 10.1006/abbi.1998.0932. View

13.

Clementi E, Brown G, Foxwell N, Moncada S . On the mechanism by which vascular endothelial cells regulate their oxygen consumption. Proc Natl Acad Sci U S A. 1999; 96(4):1559-62. PMC: 15516. DOI: 10.1073/pnas.96.4.1559. View

14.

Browne S, Ayata C, Huang P, Moskowitz M, Beal M . The cerebral metabolic consequences of nitric oxide synthase deficiency: glucose utilization in endothelial and neuronal nitric oxide synthase null mice. J Cereb Blood Flow Metab. 1999; 19(2):144-8. DOI: 10.1097/00004647-199902000-00005. View

15.

Tian W, Braunstein L, Apse K, Pang J, Rose M, Tian X . Importance of glucose-6-phosphate dehydrogenase activity in cell death. Am J Physiol. 1999; 276(5):C1121-31. DOI: 10.1152/ajpcell.1999.276.5.C1121. View

16.

Li J, Bombeck C, Yang S, Kim Y, Billiar T . Nitric oxide suppresses apoptosis via interrupting caspase activation and mitochondrial dysfunction in cultured hepatocytes. J Biol Chem. 1999; 274(24):17325-33. DOI: 10.1074/jbc.274.24.17325. View

17.

Kiessling F, Kartenbeck J, Haller C . Cell-cell contacts in the human cell line ECV304 exhibit both endothelial and epithelial characteristics. Cell Tissue Res. 1999; 297(1):131-40. DOI: 10.1007/s004410051340. View

18.

Sowa G, Liu J, Papapetropoulos A, Rex-Haffner M, Hughes T, Sessa W . Trafficking of endothelial nitric-oxide synthase in living cells. Quantitative evidence supporting the role of palmitoylation as a kinetic trapping mechanism limiting membrane diffusion. J Biol Chem. 1999; 274(32):22524-31. DOI: 10.1074/jbc.274.32.22524. View

19.

Ellerby H, Arap W, Ellerby L, Kain R, Andrusiak R, Rio G . Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med. 1999; 5(9):1032-8. DOI: 10.1038/12469. View

20.

Guo Y, Jones W, Xuan Y, Tang X, Bao W, Wu W . The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci U S A. 1999; 96(20):11507-12. PMC: 18064. DOI: 10.1073/pnas.96.20.11507. View