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      Vascular Biology of the Isoprostanes


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          Isoprostanes are a family of compounds produced from polyunsaturated fatty acids via a free-radical-catalysed mechanism. F<sub>2</sub>-isoprostanes are prostaglandin F<sub>2α</sub> isomers derived from arachidonic acid. These compounds induce potent vasoconstriction, mediated primarily by TP receptor stimulation, and in some vessels by the release of cyclooxygenase products. This vasoconstriction may be modulated by the endothelium through the release of NO. Potent vasoconstriction is also observed with E<sub>2</sub>-isoprostanes. Experimental and clinical data suggest a role for F<sub>2</sub>-isoprostanes in atherogenesis. These compounds can be detected in free forms in biological fluids as well as esterified in low-density lipoproteins or cell membranes. Their quantification represents a reliable marker of lipid peroxidation. Elevated levels of F<sub>2</sub>-isoprostanes in biological fluids in pathological conditions including atherosclerosis, ischaemia-reperfusion injury, and inflammatory vascular diseases, suggest a relationship between lipid peroxidation and such diseases. F<sub>2</sub>-isoprostanes are currently being investigated as non-invasive quantitative markers to monitor the response to anti-oxidant treatment.

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          Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage.

          It has been hypothesized that the pathogenesis of diseases induced by cigarette smoking involves oxidative damage by free radicals. However, definitive evidence that smoking causes the oxidative modification of target molecules in vivo is lacking. We conducted a study to determine whether the production of F2-isoprostanes, which are novel products of lipid peroxidation, is enhanced in persons who smoke. We measured the levels of free F2-isoprostanes in plasma, the levels of F2-isoprostanes esterified to plasma lipids, and the urinary excretion of metabolites of F2-isoprostanes in 10 smokers and 10 nonsmokers matched for age and sex. The short-term effects of smoking (three cigarettes smoked over 30 minutes) and the effects of two weeks of abstinence from smoking on levels of F2-isoprostanes in the circulation were also determined in the smokers. Plasma levels of free and esterified F2-isoprostanes were significantly higher in the smokers (242 +/- 147 and 574 +/- 217 pmol per liter, respectively) than in the nonsmokers (103 +/- 19 and 345 +/- 65 pmol per liter; P = 0.02 for free F2-isoprostanes and P = 0.03 for esterified F2-isoprostanes). Smoking had no short-term effects on the circulating levels of F2-isoprostanes. However, the levels of free and esterified F2-isoprostanes fell significantly after two weeks of abstinence from smoking (250 +/- 156 and 624 +/- 214 pmol per liter, respectively, before the cessation of smoking, as compared with 156 +/- 67 and 469 +/- 108 pmol per liter after two weeks' cessation; P = 0.03 for free F2-isoprostanes and P = 0.02 for esterified F2-isoprostanes). The increased levels of F2-isoprostanes in the circulation of persons who smoke support the hypothesis that smoking can cause the oxidative modification of important biologic molecules in vivo.
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            Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid.

            F2-isoprostanes are prostaglandin F2-like compounds that are formed nonenzymatically by free radical-induced oxidation of arachidonic acid. We explored whether oxidation of docosahexaenoic acid (C22:6omega3), which is highly enriched in the brain, led to the formation of F2-isoprostane-like compounds, which we term F4-neuroprostanes. Oxidation of docosahexaenoic acid in vitro yielded a series of compounds that were structurally established to be F4-neuroprostanes using a number of mass spectrometric approaches. The amounts formed exceeded levels of F2-isoprostanes generated from arachidonic acid by 3.4-fold. F4-neuroprostanes were detected esterified in normal whole rat brain and newborn pig cortex at a level of 7.0 +/- 1.4 ng/g and 13.1 +/- 8 ng/g, respectively. Furthermore, F4-neuroprostanes could be detected in normal human cerebrospinal fluid and levels in patients with Alzheimer's disease (110 +/- 12 pg/ml) were significantly higher than age-matched controls (64 +/- 8 pg/ml) (p < 0.05). F4-neuroprostanes may provide a unique marker of oxidative injury to the brain and could potentially exert biological activity. Furthermore, the formation of F4-neuroprostane-containing aminophospholipids might adversely effect neuronal function as a result of alterations they induce in the biophysical properties of neuronal membranes.
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              Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice.

              Oxidative modification of low density lipoprotein (LDL) has been implicated in atherogenesis. Evidence consistent with this hypothesis includes the presence of oxidized lipids in atherosclerotic lesions, the newly discovered biological properties conferred on LDL by oxidation and the acceleration of atherogenesis by in vivo delivery of the gene for 15-lipoxygenase, an oxidizing enzyme present in atherosclerotic lesions. However, it is still unknown whether oxidative stress actually coincides with the evolution of the disease or whether it is of functional relevance to atherogenesis in vivo. Isoprostanes are products of arachidonic acid catalyzed by free radicals, which reflect oxidative stress and lipid peroxidation in vivo. Elevation of tissue and urinary isoprostanes is characteristic of human atherosclerosis. Here, deficiency in apolipoprotein E in the mouse (apoE-/-) resulted in atherogenesis and an increase in iPF2alpha-VI, an F2-isoprostane, in urine, plasma and vascular tissue. Supplementation with vitamin E significantly reduced isoprostane generation, but had no effect on plasma cholesterol levels in apoE-/- mice. Aortic lesion areas and iPF2alpha-VI levels in the arterial wall were also reduced significantly by vitamin E. Our results indicate that oxidative stress is increased in the apoE-/- mouse, is of functional importance in the evolution of atherosclerosis and can be suppressed by oral administration of vitamin E.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2001
                13 April 2001
                : 38
                : 2
                : 93-103
                aLaboratoire de Pharmacologie, LSCPA EA2937, Faculté de Médecine de Grenoble, bLaboratoire de Pharmacologie, EA 2070, IFR 53, Faculté de Médecine de Reims et cUMR CNRS 5074, Faculté de Pharmacie de Montpellier, France
                51036 J Vasc Res 2001;38:93–103
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 2, References: 105, Pages: 11


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