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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2309-2315.)
© 1997 American Heart Association, Inc.

Articles

Isoprostanes: Potential Markers of Oxidant Stress in Atherothrombotic Disease

Carlo Patrono; ; Garret A. FitzGerald

From the Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Dr G.A. FitzGerald, Center for Experimental Therapeutics, University of Pennsylvania, 905 Stellar-Chance Laboratories, 422 Curie Blvd, Philadelphia, PA 19104-6100. E-mail garret{at}spirit.gcrc.upenn.edu

	Abstract

Top Abstract Introduction Mechanisms of Formation Biological Effects on Platelets... Analytical Methods F2 Isoprostane... Effects of Antioxidants Conclusions References

 
Abstract Isoprostanes are emerging as a new class of biologically active products of arachidonic acid metabolism of potential relevance to human vascular disease. Their formation in vivo seems to reflect primarily, if not exclusively, a nonenzymatic process of lipid peroxidation. Enhanced urinary excretion of 8-iso-PGF₂ has been described in association with cardiac reperfusion injury and with cardiovascular risk factors, including cigarette smoking, diabetes mellitus, and hypercholesterolemia. Besides providing a likely noninvasive index of lipid peroxidation in these settings, measurements of specific F₂ isoprostanes in urine may provide a sensitive biochemical end point for dose-finding studies of natural and synthetic inhibitors of lipid peroxidation. Although the biological effects of 8-iso-PGF₂ in vitro suggest that it and other isoeicosanoids may modulate the functional consequences of lipid peroxidation, evidence that this is likely in vivo remains inadequate at this time.

Key Words: F₂ isoprostanes • lipid peroxidation • ischemia/reperfusion • hypercholesterolemia • cigarette smoking

	Introduction

Top Abstract Introduction Mechanisms of Formation Biological Effects on Platelets... Analytical Methods F2 Isoprostane... Effects of Antioxidants Conclusions References

 
It is thought that the atherosclerotic lesion may develop as a specialized form of inflammatory response to oxidized phospholipids within the artery wall. The opposing determinants of lipid oxidation in the development of the fatty streak have been reviewed recently in this journal.¹ Although a role for oxidative modification of specific phospholipids in human atherogenesis remains to be established, the in vitro properties of oxidized LDL are consistent with its importance in monocyte/macrophage recruitment. Exposure of trapped lipoproteins to the oxidative waste products of various cellular components of the arterial wall, as well as modulation of these phenomena by the antioxidants present on the LDL particles and in the surrounding microenvironment, are thought to be among the important determinants of atherogenesis.¹ It is beyond the scope of this review to discuss the variety of biologically active lipids that result from LDL oxidation.^{1 2 3} Rather, we intend to focus on a new family of prostaglandin (PG) isomers (isoprostanes) that result from oxidative modification of arachidonic acid through a free radical–catalyzed mechanism.^{4 5} Formation of these compounds in vivo can be reliably monitored through noninvasive analytical approaches that yield sensitive and specific signals of lipid peroxidation. Moreover, the biological effects of isoprostanes might operate as transduction mechanisms linking oxidant stress to specialized forms of cellular activation, such as platelet activation and smooth muscle cell proliferation in human vascular disease.

	Mechanisms of Formation

Top Abstract Introduction Mechanisms of Formation Biological Effects on Platelets... Analytical Methods F2 Isoprostane... Effects of Antioxidants Conclusions References

 
F₂ isoprostanes are a family of PGF₂ isomers (Fig 1) first described as products of noncyclooxygenase oxidative modifications of arachidonic acid that have resulted from free-radical attack of cell membrane phospholipids⁵ or circulating LDLs.⁶ In contrast to classic PGs, which are formed through the action of PGH synthase isozymes from free arachidonic acid,⁷ F₂ isoprostanes are formed in situ from the fatty acid backbone esterified in membrane phospholipids. They are released in response to cellular activation, presumably through a phospholipase-mediated mechanism; they circulate in plasma and are excreted in the urine.^{8 9} They may circulate as the free form or as esters in phospholipids in plasma. The factors that regulate release of endogenous isoprostanes from cell membranes and interconversion between the free and esterified forms are presently poorly understood.

View larger version (16K): [in this window] [in a new window]   Figure 1. Four classes of F2 isoprostanes that may be formed by free-radical attack on arachidonic acid. 8-iso-PGF2 may also be formed in a COX-dependent manner. PG indicates prostaglandin; COX, cyclooxygenase; and FR, free radical.

Given the ubiquitous distribution of the precursor arachidonic acid, isoprostane biosynthesis can occur in virtually all of the cellular players of the atherosclerotic lesion, including monocytes.¹⁰ Indeed, coincubation of activated human monocytes with LDL resulted in a time-dependent formation of the F₂ isoprostane 8-iso-PGF₂ but not of PGE₂ or thromboxane (TX) B₂, coincident with LDL oxidation.¹⁰ The increase in 8-iso-PGF₂ formation was associated with an increase in thiobarbituric acid–reactive substance (TBARS) and hydroperoxide levels. This phenomenon was prevented by the oxygen free-radical scavengers SOD and BHT but not by cyclooxygenase inhibitors.¹⁰ Consistent with these in vitro studies, immunolocalization of 8-iso-PGF₂ in the monocytes/macrophages and vascular smooth muscle cells of human atherosclerotic tissue has recently been described in specimens obtained during carotid endarterectomy.¹¹

In addition to a cyclooxygenase-independent mechanism of formation involving peroxidative attack on arachidonic acid, in which bicyclic endoperoxide intermediates are formed that are then reduced to give rise to isoprostanes such as 8-iso-PGF₂, there is recent evidence that 8-iso-PGF₂, unlike other F₂ isoprostanes, can be produced as a minor product of the cyclooxygenase activity of platelet PGH synthase-1 in response to platelet stimulation with collagen, thrombin, or arachidonate (Fig 1).^{9 12} Activated platelets can generate 8-iso-PGF₂ and TXB₂ in a molar ratio of 1:1000.^{9 12} A second enzyme endowed with cyclooxygenase activity, PGH synthase-2, can be expressed in different cell types in response to inflammatory and mitogenic stimuli (reviewed in Reference 7⁷ ). Induction of PGH synthase-2 in human monocytes by concanavalin A, phorbol ester, or bacterial lipopolysaccharide was associated with cyclooxygenase-dependent formation of 8-iso-PGF₂ and PGE₂ in a molar ratio ranging from 1:5 to 1:30.^{10 13} Dexamethasone, an inhibitor of PGH synthase-2 induction, and L-745337, a selective inhibitor of the cyclooxygenase activity of monocyte PGH synthase-2,¹⁴ dose-dependently suppressed 8-iso-PGF₂ and PGE₂ formation with similar potency.^{10 13}

Although the contribution of cyclooxygenase-dependent mechanisms to the formation of 8-iso-PGF₂ in vivo appears to be negligible under physiological circumstances,⁹ the general assumption that measurements of this F₂ isoprostane in plasma or urine are a reflection of nonenzymatic lipid peroxidation requires validation in clinical settings of platelet and/or monocyte activation (see below).

	Biological Effects on Platelets and Vascular Cells

Top Abstract Introduction Mechanisms of Formation Biological Effects on Platelets... Analytical Methods F2 Isoprostane... Effects of Antioxidants Conclusions References

 
The formation of isoprostanes in lipid bilayers by a free radical–catalyzed mechanism may contribute importantly to alterations in the fluidity and integrity of cellular membranes. In addition, 8-iso-PGF₂ is a potent vasoconstrictor¹⁵ and induces DNA synthesis in vascular smooth muscle cells, perhaps through interaction with receptors that are distinct from but closely related to PGH₂/TXA₂ receptors.¹⁶ Although a functional role for isoprostanes in atherogenesis remains to be established, discriminant production of this isoprostane by both reactive oxygen species and monocyte PGH synthase 2 within atherosclerotic plaques renders it a candidate molecule to transduce, at least in part, the effects of lipid peroxidation and inflammation on vascular dysfunction. Formation of isoprostanes in situ in the phospholipid bilayer may modify cell function. Subsequent cleavage may release products, such as 8-iso PGF₂, that modify aspects of platelet function such as adhesive reactions and activation by low concentrations of other agonists. Formation of isoprostanes in monocytes may modify aspects of their function, such as expression of tissue factor. Similarly, formation of isoprostanes in oxidized LDL may result in their uptake by monocytes/macrophages, resulting in the formation of foam cells. Isoprostanes may also modify vascular smooth muscle cell function and accumulate in these cells in proximity to atherosclerotic plaques (Fig 2).

View larger version (34K): [in this window] [in a new window]   Figure 2. Potential sites of isoprostane formation and cellular targets of 8-iso-PGF2 of relevance to atherothrombosis. ELAM indicates endothelial leukocyte adhesion molecule; PGI2, prostacyclin; PAF, platelet-activating factor; TX, throm- boxane; and VCAM, vascular cell adhesion molecule.

Concentrations of 8-iso-PGF₂ in the range of 1 nmol/L to 1 µmol/L induce a dose-dependent increase in platelet shape change, calcium release from intracellular stores, and inositol phosphates.^{17 18} Moreover, 8-iso-PGF₂ causes dose-dependent, irreversible platelet aggregation in the presence of concentrations of collagen, ADP, arachidonic acid, and PGH₂/TXA₂ analogues that, when acting alone, fail to aggregate platelets.¹⁸ Although these effects are prevented by PGH₂/TXA₂ receptor antagonists and 8-iso-PGF₂ may cross-desensitize biochemical and functional responses to thromboxane mimetics,¹⁹ 8-iso-PGF₂ fails to activate either of the TX receptor isoforms described in platelets at concentrations that typically circulate during syndromes of oxidant stress.¹⁸ The ability of 8-iso-PGF₂ to amplify the aggregation response to subthreshold concentrations of platelet agonists may be relevant to settings where platelet activation and enhanced free-radical formation coincide.¹⁸ Similarly, another F₂ isoprostane 12-epi-PGF₂, activates PGF₂ receptors and stimulates proliferative responses in fibroblasts.²⁰ However, whether the local concentrations of isoprostanes achieved in vivo are sufficient to allow them to act as an incidental ligand for prostanoid receptors or whether specific isoprostanes receptors with higher affinity for them might exist remains to be established.

	Analytical Methods

Top Abstract Introduction Mechanisms of Formation Biological Effects on Platelets... Analytical Methods F2 Isoprostane... Effects of Antioxidants Conclusions References

 
Both stable-isotope dilution assays using gas chromatography/mass spectrometry (GC/MS) and immunoassays for 8-iso-PGF₂ have been developed.^{9 21} Although only one metabolite of 8-iso-PGF₂ has been identified to date,²² measurable concentrations of the unmetabolized compound are present in peripheral venous blood, and a relatively reproducible fraction is excreted unchanged in human urine, with no detectable circadian variation. Morrow and Roberts have described GC/MS–based methods for quantifying levels of "total" free F₂ isoprostanes in plasma and of F₂ isoprostanes esterified to plasma lipids. Moreover, they have identified a tetranor dicarboxylic acid derivative as a potential urinary metabolite of the F₂ isoprostanes⁸ and reported a linear correlation between the estimated urinary excretion of uncharacterized isoprostane metabolites and circulating concentrations of free F₂ isoprostanes.²¹ The development of specific assays for such metabolites may be of particular value as indices of isoprostane generation in plasma rather than as substitutes for specific measurement of F₂ isoprostanes in urine. The ex vivo artifactual formation of unmetabolized compounds resulting from auto-oxidation of lipids is much less likely in urine than in plasma. Because 8-iso-PGF₂ represents a major component of the "total" F₂ isoprostanes measured in plasma or urine, any cyclooxygenase-dependent formation of this compound in a specific pathophysiological setting may contribute importantly to such an integrated signal, as well as to specific measurements of 8-iso-PGF₂ itself. Given that as many as 64 PGF isomers may theoretically result from free radical–catalyzed transformation of arachidonic acid,⁵ analysis of distinct isomers with the use of specific internal standards would seem preferable to estimates of "total" isoprostane biosynthesis. Selective analysis of an isomer, distinct from 8-iso PGF₂, that cannot be formed enzymatically, such as IPF₂-I, can provide an additional analytical tool to probe the nonenzymatic nature of F₂ isoprostane formation in vivo.²³

Given that mass spectrometers are confined to relatively specialized laboratories, the application of this methodology to clinical investigation is likely to remain restricted. Both 8-iso-PGF₂ and IPF₂-1 appear chemically stable in urine frozen at -70°C for as long as 3 months, thus allowing samples to be shipped to a reference laboratory. An alternative approach is to use an immunoassay. Using an antibody that has been described, we have previously published a striking correlation between immunoactive 8-iso-PGF₂ and levels measured by GC/MS.⁹ However, given that other isomeric species of PGF might be expected to correlate with levels of 8-iso-PGF₂ in these samples and that few have been synthesized to check for cross-reactivity, one cannot state with certainty that 8-iso-PGF₂ immunoreactivity is restricted to 8-iso-PGF₂. Similarly, no antibodies have been checked for cross-reactivity with isoprostane metabolites, which are largely unidentified. Similar caveats apply to the commercialized reagent for the 8-iso-PGF₂ immunoassay (Cayman Biochemicals, Ann Arbor, Mich). The source of 8-iso-PGF₂ in urine is likely to be conditional on the experimental setting or the disease under study, as is the case with classic PGs.²⁴ However, we assume that urinary excretion of unmetabolized 8-iso-PGF₂ may also reflect oxidant stress in tissues other than the kidney.

No systematic comparisons have been reported of F₂ isoprostane measurements with other indices of oxidant stress. However, it should be emphasized that the latter suffer from major limitations in assessing the actual rate of lipid peroxidation in vivo. This has been measured by various methods, including the analysis of lipid hydroperoxides, conjugated dienes, reactive aldehydes, and estimation of expired hydrocarbons (reviewed in Reference 25²⁵ ). A widely used index of peroxidation is the measurement of malondialdehyde (MDA) by the thiobarbituric acid assay. However, due to the uncertainty in the structure of the derivative and the lack of specificity of the assay, the level of MDA is usually expressed as TBARS. Development of a GC/MS assay for MDA has recently demonstrated that the commonly used thiobarbituric acid assay for MDA overestimates actual MDA levels by >10-fold, possibly resulting from cross-reactivity with other aldehydes and the harsh conditions used in sample preparation.²⁶ Moreover, MDA is a byproduct of cyclooxygenase activity in platelets,²⁷ and persistent platelet activation in vivo is a common feature of many clinical syndromes associated with enhanced lipid peroxidation (see below). Similarly, the accuracy of exhaled pentane as an index of in vivo lipid peroxidation has been questioned.²⁸

Lipoprotein oxidation is unlikely to occur in plasma because of the presence of high concentrations of antioxidants and proteins that chelate metal ions.²⁹ It is more likely to occur in a microenvironment where antioxidants can become depleted and lipoproteins are exposed to oxidative stress. Because of the substantial uncertainly as to the most likely biochemical pathways involved in LDL oxidation within the artery wall,²⁹ it is unclear whether the wide variations reported in the susceptibility of LDL from different individuals to oxidation ex vivo have any relevance to the extent of LDL oxidation in vivo.

	F2 Isoprostane Formation in Human Vascular Disease

Top Abstract Introduction Mechanisms of Formation Biological Effects on Platelets... Analytical Methods F2 Isoprostane... Effects of Antioxidants Conclusions References

 
A limited number of studies have been completed during the past 2 years addressing the formation of F₂ isoprostanes in clinical settings putatively associated with oxidative damage, either as a result of acute ischemia/reperfusion or long-standing metabolic abnormalities. Free radicals are thought to mediate the reperfusion injury that characterizes thrombolytic therapy after myocardial infarction.^{30 31 32} The myocardial stunning described in animal models of coronary occlusion/reperfusion^{33 34 35} and in some patients undergoing thrombolytic therapy^{36 37} is considered to be a manifestation of this phenomenon. Delanty et al³⁸ have recently reported that urinary 8-iso-PGF₂ excretion was unchanged following thrombotic circumflex artery occlusion in a canine model of coronary thrombolysis but increased significantly immediately following reperfusion with thrombolytic drugs. Moreover, urinary 8-iso-PGF₂ was increased in patients with acute myocardial infarction given thrombolytic therapy (mostly streptokinase) when compared with both age-matched, healthy control subjects and patients with stable coronary heart disease.³⁸ The global myocardial reperfusion injury that may follow coronary artery bypass grafting (CABG) is also thought to result from free-radical generation in the reperfused vasculature.^{39 40} In the study of Delanty et al,³⁸ urinary excretion of 8-iso-PGF₂ increased following elective CABG and peaked 15 minutes after global myocardial reperfusion. The increase in urinary 8-iso-PGF₂ during coronary reperfusion corresponded both in time and magnitude to changes in spin-trapping of -phenyl-N-butylnitrone adducts, as detected by electron paramagnetic resonance in two patients.³⁸ Interestingly, increased levels of urinary 8-iso-PGF₂ have also been detected following carotid reperfusion in patients undergoing endarterectomy (D. Praticò et al, 1997, unpublished results) and in patients undergoing coronary angioplasty.⁴¹ The functional consequences of enhanced formation of this biologically active eicosanoid have not yet been explored. However, these recent findings provide a rationale for dose-finding studies of natural or synthetic antioxidants using urinary 8-iso-PGF₂ as a biochemical end point. Enhanced formation of 8-iso-PGF₂ might be expected in patients with acute ischemic stroke, a condition in which formation of free radicals is likely to occur. However, in a recent study of 62 patients with acute ischemic stroke from whom at least two consecutive 6-hour urine samples were obtained during the first 72 hours after the onset of symptoms, no consistent changes in immunoreactive 8-iso-PGF₂ excretion were detected, in contrast with the isosodic increases in TX metabolite excretion.⁴² Increased oxidant stress might occur as an early, transient event that could be largely missed by the timing of urine sampling, or the signal-to-noise ratio might be too small to be detected at a distance from its source. These negative findings are useful, however, in demonstrating that in a clinical condition where platelets are clearly activated in an episodic fashion,⁴³ there are no apparently concurrent changes in 8-iso-PGF₂ formation and excretion, thus implying trivial if any contribution from platelet cyclooxygenase activity.

Persistently enhanced formation of F₂ isoprostanes has been reported in association with several cardiovascular risk factors, including cigarette smoking,^{21 44} diabetes mellitus,^{45 46 47} and hypercholesterolemia,^{48 49} conditions putatively characterized by increased lipid peroxidation in response to the various constituents of cigarette smoke or complex metabolic abnormalities. Accelerated LDL oxidation,²⁹ as well as platelet activation,⁵⁰ are common features of these conditions. In chronic cigarette smokers, both plasma levels of F₂ isoprostanes and urinary excretion of 8-iso-PGF₂ are increased in comparison with sex- and age-matched nonsmokers.^{21 44} Moreover, there is a relationship between the number of cigarettes smoked and excreted 8-iso-PGF₂ levels.⁴⁴ Smoking had no short-term effects on circulating levels of F₂ isoprostanes.²¹ However, the levels of free and esterified F₂ isoprostanes in plasma²¹ and of 8-iso-PGF₂ in urine⁴⁴ fell significantly after cessation of smoking. Low-dose aspirin (75 mg/d for 10 days) failed to suppress urinary 8-iso-PGF₂ excretion despite suppression of platelet cyclooxygenase-1 activity and TX metabolite excretion.⁴⁴

Although diabetes mellitus is a clearly established risk factor for cardiovascular disease, the mechanism(s) responsible for accelerated atherogenesis remain elusive. Altered lipoprotein levels; changes in lipoprotein composition, possibly affecting LDL binding to its receptors; and reduced LDL clearance resulting from impaired receptor recognition of glycated LDL have been described in diabetic patients (reviewed in Reference 51⁵¹ ). Moreover, both high glucose levels and protein glycation enhance LDL oxidation by metal ions, and these reactions also yield advanced glycosylation end (AGE) products.^{29 51} In fact, LDLs isolated from non–insulin-dependent diabetics (NIDDM) contain higher levels of AGE products and conjugated dienes and are more easily oxidized by copper than is native LDL.⁵² In addition, plasma from patients whose insulin-dependent diabetes mellitus (IDDM) is poorly controlled has less antioxidant capacity.⁵³ Consistent with the concept of enhanced lipid peroxidation in diabetes, Gopaul et al⁴⁵ have reported that the average concentration of esterified 8-iso-PGF₂ in plasma from 39 patients with NIDDM was approximately threefold higher than in healthy individuals. However, increased plasma levels of 8-iso-PGF₂ were not functions of hyperglycemia or hyperlipidemia.⁴⁵ Catella-Lawson et al⁴⁶ have recently reported a trend toward increased urinary 8-iso-PGF₂ excretion in a group of 18 diabetics, with statistically significant elevations in patients presenting with diabetic ketoacidosis. Furthermore, increased oxidizability of LDL in diabetics was more readily reflected by 8-iso-PGF₂ than by conjugated diene formation.⁴⁶ In the study of Ciabattoni et al,⁴⁷ urinary immunoreactive 8-iso-PGF₂ was significantly higher in a group of 55 NIDDM and 23 IDDM patients than in age-matched control subjects by approximately twofold. Tight metabolic control was associated with a statistically significant reduction in 8-iso-PGF₂ excretion, by 40%.⁴⁷

High cholesterol levels have an established role in the development of atherosclerotic vascular lesions and in cardiovascular events induced by vascular occlusion.⁵⁴ Evidence for this role has been inferred from both epidemiological and interventional studies.^{55 56} However, occlusive events may occur in the absence of grossly elevated cholesterol levels, particularly in the presence of other risk factors, such as cigarette smoking, diabetes mellitus, and hypertension. A link between moderately elevated cholesterol levels and other risk factors for cardiovascular disease has been proposed to involve oxidative modifications of LDL, although direct evidence of its functional importance in human atherogenesis remains to be provided.² Oxidatively modified LDL has been found in foam cells and atherosclerotic plaques and has been shown to acquire a variety of properties possibly relevant to the process of atherogenesis.^{2 3} Moreover, increased susceptibility of LDL to in vitro oxidation has been demonstrated in hypercholesterolemic patients.^{57 58}

Type IIa hypercholesterolemia is also characterized by platelet activation in vivo, as reflected by enhanced TX metabolite excretion.⁵⁹ Immunoreactive 8-iso-PGF₂ is altered in patients with hypercholesterolemia and appears to contribute to platelet activation in this setting.⁴⁸ Paired measurements of 8-iso-PGF₂ and 11-dehydro-TXB₂ in 40 hypercholesterolemic patients and 40 age- and sex-matched control subjects revealed a highly significant linear correlation between the two. Urinary 8-iso-PGF₂ was significantly higher in hypercholesterolemic patients than in control subjects by twofold to threefold, and its rate of excretion was directly correlated with LDL cholesterol levels and inversely related to the vitamin E content of LDL. Urinary immunoreactive 8-iso-PGF₂ was unchanged following a 2-week dosing with aspirin or indobufen, a reversible cyclooxygenase inhibitor, despite complete suppression of TX metabolite excretion. Consistent with the hypothesis of enhanced 8-iso-PGF₂ formation's contribution to platelet activation in this setting, dose-dependent suppression of the former by vitamin E supplementation was associated with comparable reductions in 11-dehydro-TXB₂ excretion.⁴⁸ Thus, enhanced nonenzymatic peroxidation of arachidonic acid may provide a biochemical link between oxidant stress and platelet activation in the setting of hypercholesterolemia. Using MS, Reilly et al⁴⁹ demonstrated that both urinary IPF₂-I and 8-iso-PGF₂ levels were elevated in patients with homozygous and heterozygous familial hypercholesterolemia. Excretion of the two isoprostanes was highly correlated within both groups of hyperlipidemic patients. Interestingly, levels of 8-iso-PGF₂ esterified in circulating LDL correlated with urinary levels of this isoprostane in patients with familial homozygous hypercholesterolemia.

The studies of 8-iso-PGF₂ formation conducted so far appear to exclude a significant contribution from a cyclooxygenase-dependent mechanism of biosynthesis in vivo. This is supported by 1) dissociation of 8-iso-PGF₂ and 11-dehydro-TXB₂ excretion in acute ischemic stroke; 2) no effects of aspirin and other nonspecific cyclooxygenase inhibitors on urinary 8-iso-PGF₂ in healthy subjects, acute stroke patients, and hypercholesterolemic subjects; and 3) correlation between urinary 8-iso-PGF₂ and IPF₂-I in the settings of percutaneous transluminal coronary angioplasty and hypercholesterolemia, as well as between levels of both isoprostanes in atherosclerotic plaque. The availability of selective inhibitors of PGH synthase-2 will permit further definition of the potential contribution of this pathway to formation of 8-iso-PGF₂, particularly in the setting of inflammation or increased cellular proliferation, where induction of this enzyme might be anticipated.

	Effects of Antioxidants

Top Abstract Introduction Mechanisms of Formation Biological Effects on Platelets... Analytical Methods F2 Isoprostane... Effects of Antioxidants Conclusions References

 
Numerous epidemiological studies have shown that dietary intake of vitamin E is inversely associated with the risk of cardiovascular disease, though few randomized intervention trials have prospectively tested the cardiovascular benefit from vitamin treatment.⁶⁰ In general, the epidemiological studies have been interpreted to suggest that prevention of cardiovascular disease requires large amounts of vitamin E, in excess of the conventional dietary intake. However, there is substantial uncertainty as to the optimal dose of vitamin E supplementation, largely because of inadequate biochemical end points for its efficacy. This is reflected in a wide range of doses tested in randomized clinical trials, from as low as 50 mg daily of racemic -tocopherol to as high as 500 mg daily.^{60 61} A number of mechanisms have been suggested to contribute to the putative beneficial effects of vitamin E, including inhibition of LDL oxidation and prevention of fatty streak formation (reviewed in Reference 29²⁹ ), stabilization of coronary lesions,⁶¹ a direct antiplatelet effect,⁶² or improvement of endothelium-dependent vasodilation.⁶³

Limited information is available on the effects of vitamin E on F₂ isoprostane formation. Thus, Reilly et al⁴⁴ have reported no significant changes in urinary 8-iso-PGF₂ excretion following a 5-day course of vitamin E supplementation in a limited number of moderate (100 U/d) or heavy (800 U/d) smokers. In contrast, vitamin C (2 g/d) alone or in combination with vitamin E significantly depressed urinary 8-iso-PGF₂ in heavy smokers to a comparable level achieved by smoking cessation.⁴⁴ Two-week dosing with vitamin E (100 to 600 mg daily) was found to reduce immunoreactive 8-iso-PGF₂ excretion in a dose-dependent fashion in hypercholesterolemic subjects, with all measurements falling within the range of healthy subjects at 600 mg daily.⁴⁸ Similar changes in urinary immunoreactive 8-iso-PGF₂ have been reported following high-dose vitamin E supplementation in NIDDM patients.⁴⁷ Clearly, controlled studies are needed to assess the dose-response relationship and the time dependence of the effects of antioxidant vitamins on F₂ isoprostane formation. However, the results of the available studies do provide a rationale for dose-ranging studies based on measurements of urinary 8-iso-PGF₂ in appropriate target populations. This may help resolve some of the uncertainty about the optimal dose of vitamin E supplementation in various clinical settings and provide a more rational basis for disease selection for large-scale interventional trials.

	Conclusions

Top Abstract Introduction Mechanisms of Formation Biological Effects on Platelets... Analytical Methods F2 Isoprostane... Effects of Antioxidants Conclusions References

 
Isoprostanes are emerging as a new class of biologically active products of arachidonic acid metabolism of potential relevance to human vascular disease. Their formation seems to reflect primarily, if not exclusively, a nonenzymatic process of lipid peroxidation in vivo. Besides the F₂ isoprostanes extensively discussed in this review, isomers of other PGs and leukotrienes have also been recently described.^{64 65} Enhanced urinary excretion of 8-iso-PGF₂ has been characterized in association with cardiac reperfusion injury and cardiovascular risk factors, including cigarette smoking, diabetes mellitus, and hypercholesterolemia. Besides providing a reliable, noninvasive index of lipid peroxidation in these settings, measurements of specific F₂ isoprostanes, such as IPF₂-I and 8-iso-PGF₂, in urine may provide sensitive biochemical end points for dose-finding studies of natural and synthetic inhibitors of lipid peroxidation. Although the biological effects of 8-iso-PGF₂ in vitro suggest that it and other isoeicosanoids^{64 65} may modulate the functional consequences of lipid peroxidation, evidence that this is likely in vivo remains inadequate at this time. However, the analytical and pharmacological tools are now available to explore this hypothesis, as outlined in this review.

	Acknowledgments

 
This work was supported by grants from the National Institutes of Health, Bethesda, Md (1P50HL54500 and MO1 RR 00040 to G.A.F.), from the Wellcome Trust (to G.A.F.), Bayer AG (to C.P.), and a BIOMED grant from the European Union (BMHI-CT93-1533 to C.P.). Dr FitzGerald is the Robinette Foundation Professor of Cardiovascular Medicine. The expert editorial assistance of Gail Vogel and Susan Weber is gratefully acknowledged.

Received February 18, 1997; accepted April 29, 1997.

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Top Abstract Introduction Mechanisms of Formation Biological Effects on Platelets... Analytical Methods F2 Isoprostane... Effects of Antioxidants Conclusions References

 
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