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Explore the impact of nitric oxide on lipid oxidation processes in the body, identifying key reactions and products. Learn about the role of enzymes and how nitric oxide can inhibit lipid peroxidation to maintain vascular health.
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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
Nitric Oxide is a Free Radical N=O NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.2
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
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
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
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
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
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
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
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
Nitric oxide reaction with lipid peroxyl radicals NO LOO LOONO H2O [LONO2] LOOH + NO2- LONO2 NO [L(O)NO2] NO LONO NO2- L(O)NO2 NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.11
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
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
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
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
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
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
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
Site of lipoxygenase inhibition by NO NO & LPOSociety For Free Radical Biology and Medicine O’Donnell et al.19
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
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