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Nitric Oxide and Lipid Peroxidation

Nitric Oxide and Lipid Peroxidation. Valerie B. O’Donnell a , Neil Hogg b and Victor M. Darley Usmar c. b Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, WI USA. c Department of Pathology, University of Alabama at Birmingham, AL USA. a Dept of Med. Biochem.

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Nitric Oxide and Lipid Peroxidation

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  1. Nitric Oxide and Lipid Peroxidation Valerie B. O’Donnella, Neil Hoggb and Victor M. Darley Usmarc bBiophysics Research Institute, Medical College of Wisconsin, Milwaukee, WI USA. cDepartment of Pathology, University of Alabama at Birmingham, AL USA aDept of Med. Biochem. University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. Ph: 0044-2920-748447 Fax: 0044-2920-744905 Email: o-donnellvb@cardiff.ac.uk NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.1

  2. Nitric Oxide is a Free Radical N=O NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.2

  3. Nitric oxide is not particularly oxidizing.Nitric oxide is (infinitely) stable*.Nitric oxide does not rapidly react with organic molecules. *In the absence of dioxygen. NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.3

  4. The Nitric Oxide ‘Radical’ and some of its stable end-products •N=O…nitric oxide -O-N=O…nitrite RO-N=O…alkyl nitrite RS-N=O…nitrosothiol NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.4

  5. Reactions of •NO with Other Free Radicals Oxidation of NO to nitrite: 4 NO+ O=O +2H2O  4HNO2 Nitric oxide reaction with organic peroxyl radicals: NO+ ROO ROONO  ?? NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.5

  6. Lipid Peroxidation LOO + LH + O2 LOO + LOOH LOO is the central and rate-limiting species of lipid peroxidation NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.6

  7. LOOH Metal or enzyme LH LH L LOO LOO L LOO O2 O2 AOO O2 LOOH LOOH GPx LH GPx LOH LOH Propagation Propagation Initiation Non-enzymatic lipid oxidation NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.7

  8. Lipid peroxidation products in an atherosclerotic lesion are both enzymatically and non-enzymatically produced. Foam cell 15-LOX  Necrotic core lipid hydroxides, hydroperoxides, aldehydes, epoxides, ketones, ceroid, isoprostanes Fibrous cap NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.8

  9. Location of lipid oxidation enzymes in the vasculature LOX: lipoxygenase PGHS: prostaglandin H synthase Smooth muscle: 12-LOX Monocyte: PGHS-1,2 5, 15-LOX Platelet: PGHS-1 12-LOX Neutrophil: PGHS-1,2 5,12-LOX Endothelium PGHS-1 NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.9

  10. Lipid oxidation enzymes are upregulated during vascular disease. * Inhibition of 12-LOX restores blood pressure in Angiotensin- II dependent hypertensive rats. * Increased products of PGHS in hypertensive rats, and PGHS inhibition restores blood pressure in humans and rats. * Smooth muscle 12-LOX  in hypertension * Platelet 12-LOX  in hypertension * Foam cell/macrophage 15-LOX  in atherosclerosis. NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.10

  11. Nitric oxide reaction with lipid peroxyl radicals NO LOO LOONO H2O [LONO2] LOOH + NO2- LONO2 NO [L(O)NO2] NO LONO NO2- L(O)NO2 NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.11

  12. NO L(O)NO2 LOONO O2 O2- NO ONOO- HONO NO2 O2 LOOH LH L LOO e-, H+ NO2, ONOO- LNO2 Reactions between NO-derived reactive nitrogen species and unsaturated lipid NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.12

  13. Nitric oxide inhibition of lipid oxidation coincides with fast rates of NO uptake during ABAP-dependent linoleate oxidation. (A) (B) 0.6 200 0.2 ABAP Oxygen (µM) NO (µM) 100 -0.2 [ NO] = 0.9 µM added at vertical lines to 7.3 mM linoleate in 0.5% cholate, 11 mM ABAP 0 -0.6 0 400 800 1200 Time/s NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.13

  14. LOO + NO  LOONO LO + NO2 LONO2 LOOH OLOO + NO OLOONO  OLONO2 Mechanism of Inhibition of LDL Oxidation by NO Two NO consumed for each LOO 4 NO + 2LOO + H2O 2HNO2 + LONO2 + LONO NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.14

  15. Cholesteryl Ester Triglyceride Phospholipid Apolipoprotein B O2 LH Oxidant •NO2 O2 L• •NO2 LH LOO• LNO2 •NO2 L• •NO LOOH -Tocopherol L(O)NO2 Cholesterol •NO NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.15

  16. NO and LDL Oxidation: The effect of HPODE Lag time of LDL (125 g/ml) oxidation by Cu(II) (20 M) with and without HPODE (5 M) NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.16

  17. a -tocopherol (1 µM) ABAP 300 NO (1 µM) 200 [Oxygen]/µM T inh 100 T inh 0 0 200 400 600 800 1000 1200 Time/s Comparison of nitric oxide and tocopherol inhibition of linoleate oxidation. Oxidation of linoleate (7.3 mM) by ABAP (11 mM) NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.17

  18. Nitric oxide is consumed by rabbit 15-lipoxygenase during oxidation of linoleate. Add figure caption NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.18

  19. Site of lipoxygenase inhibition by NO NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.19

  20. Lox NO sGC cGMP 100 cGMP (% control) 50 ** 0 LOX control AA, 5 µM AA, 5 µM, LOX Activation of LOX inhibits activation of sGC by NO NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.20

  21. Further Reading: Darley-Usmar, VM et al., (1992) Free Radic. Res. Commun. 17, 9-20 Graham, A et al., (1993) FEBS Lett.330, 181-185 Rubbo, H et al., (1994) J. Biol. Chem.265, 26066-26075 Hogg, N et al., (1995) J. Lipid Res. 36, 1756-1762 Struck, N et al., (1995) FEBS Lett361, 291-294 O’Donnell, VB et al., (1997) Biochemistry36, 15216-15223 O’Donnell, VB et al., (1999) Chem. Res. Toxicol.12, 83-92 O’Donnell, VB et al., (1999) J. Biol. Chem.274, 20083-20091 Hogg, N & Kalyanaraman, B (1999) Biochim. Biophys. Acta.1411, 378-384 Rubbo, H et al., (2000) J. Biol. Chem.275, 10812-10818 O’Donnell, VB & Freeman, BA (2001) Circ. Res.88, 16-25 NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.21

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