(Circulation. 1997;95:2492.)
© 1997 American Heart Association, Inc.
Articles |
8-Epi PGF2
Generation During Coronary Reperfusion
A Potential Quantitative Marker of Oxidant Stress In Vivo
the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia; Philadelphia Biomedical Research Institute, King of Prussia, Pa (S.T.O.); the Department of Cardiothoracic Surgery, Mater Hospital, Dublin, Ireland (J.F.M., A.E.W.); and the Center for Cardiovascular Science, RCSI, Dublin, Ireland (D.J.F.).
Correspondence to Dr G.A. FitzGerald, Center for Experimental Therapeutics, 905 Stellar-Chance Laboratories, 422 Curie Blvd, University of Pennsylvania, Philadelphia, PA 19104. E-mail garret{at}spirit.gcrc.upenn.edu
Abstract
Background Myocardial reperfusion is believed to be associated with free radical injury. However, indexes of oxidative stress in vivo have been limited by their poor specificity and sensitivity. Isoprostanes are stable products of arachidonic acid formed in a nonenzymatic, free radical–catalyzed manner. We have developed a sensitive and specific assay for one of these compounds, 8-epi prostaglandin (PG) F2
.
Methods and Results To address its utility as an index of oxidative stress during coronary reperfusion, we measured urinary levels by gas chromatography/mass spectrometry in a canine model of coronary thrombolysis, in patients with acute myocardial infarction treated with thrombolytic therapy, and in patients after elective coronary artery bypass surgery. Urinary 8-epi PGF2 was unchanged after circumflex artery occlusion in a canine model of coronary thrombolysis (n=13; 437.2±56.4 versus 432.7±55.2 pmol/mmol creatinine) but increased significantly (P<.05) immediately after reperfusion (553.8±64.7 pmol/mmol). Urinary levels were increased (P<.001) in patients (n=12) with acute myocardial infarction given lytic therapy (265.8±40.8 pmol/mmol) compared with age-matched control subjects (n=20; 91.5±11.8 pmol/mmol) and patients with stable coronary disease (n=20; 95.7±6.3 pmol/mmol). Preoperative levels rose from 113.2±11.8 to 248.2±86.3 pmol/mmol at 30 minutes into revascularization to 332.2±82.6 pmol/mmol by 15 minutes after global myocardial reperfusion (P<.05) and dropped to 181.2±50.4 pmol/mmol at 30 minutes and 120.2±9.9 pmol/mmol at 24 hours after bypass surgery (n=5). Corresponding changes in spin adduct formation, found with electron paramagnetic resonance, were noted in 2 patients.
Conclusions These data support the hypothesis that free radical generation occurs during myocardial reperfusion. Measurement of isoprostane production may serve as a noninvasive index of oxidative stress.
Key Words: reperfusion • free radicals • prostaglandins
Although oxidant stress has been suggested to contribute to the pathophysiology of diseases as diverse as cancer, cystic fibrosis, and Alzheimer's disease, little definitive information is available as to the importance of this process in vivo. This derives in part from the limitations of available indexes of free radical–catalyzed events in vivo. Traditional approaches have involved the use of assays directed against nonspecific or unstable analytes such as malondialdehyde or lipid hydroperoxides1 2 or the assessment of either spin adduct formation or of lipoprotein oxidizability induced ex vivo.3 4
Arachidonic acid is subject to oxidative modification.5 F2-isoprostanes, a family of free radical catalyzed prostaglandin F2-isomers, have been detected in human plasma and urine.6 7 8 One of these compounds, 8-epi PGF2, is a vasoconstrictor and a mitogen, effects that are prevented by thromboxane A2 receptor antagonists.9 10 Using gas chromatography/mass spectrometry,11 we have developed a specific and sensitive assay for 8-epi PGF2 and are exploring its potential utility as a specific, chemically stable, noninvasive index of free radical generation in vivo.
Free radicals are thought to mediate reperfusion injury following thrombolytic therapy for myocardial infarction.12 13 14 15 The myocardial stunning that characterizes animal models of coronary occlusion or reperfusion16 17 18 and some patients after thrombolytic therapy19 20 is also thought to be a manifestation of this phenomenon. Global myocardial reperfusion injury that may follow CABG21 22 may also result from free radical generation in the reperfused vasculature. Epidemiological evidence has related cardiovascular risk to dietary consumption of antioxidant vitamins,23 24 although this is controversial.25 26 More recently, varied doses of vitamin E have been reported to modulate clinical outcome in patients with established coronary artery disease.27
The present studies document the stability of 8-epi PGF2 excretion in urine under physiological conditions. They are then extended to provide evidence for elevated urinary 8-epi PGF2 in three settings of myocardial reperfusion. Isoprostane formation was increased in a canine model of coronary thrombolysis, in patients with acute myocardial infarction treated with thrombolytic drugs, and after clamp release in patients undergoing CABG. These results suggest that urinary 8-epi PGF2 may represent a noninvasive in vivo index of free radical generation. This would be a useful adjunct to the evaluation of putative antioxidant drugs in cardiovascular disease.
Methods
Animal Study
This study was reviewed and approved by the Animal Care Committee at the University College Dublin. The model used was a closed-chest, canine model of coronary thrombolysis as previously described.28 29 Briefly, male mongrel dogs (n=7) were anesthetized with pentobarbital 30 mg/kg and supported on a ventilator. Through a thoracotomy, a needle electrode was implanted in the circumflex coronary artery distal to a Doppler flow probe. The terminals of the electrode and flow probe were brought to the surface in the subcutaneous pouch, and the dog was allowed to recover. Five to 7 days after surgery, the dog was sedated, and the terminals of the electrode and flow probe were recovered. The flow probe was connected to a Doppler flowmeter in series with a polygraph for continuous recording of coronary blood flow velocity. A 200-µA current was passed through the electrode to induce endothelial and coronary thrombosis. Thrombotic occlusion of the coronary artery, detected as abolition of the Doppler flow signal, occurred after 1 to 2 hours, and the current was discontinued 30 minutes later. Two hours after complete coronary occlusion, rt-PA 10 µg·kg-1·min-1 was administered by intravenous infusion and continued until 10 minutes after reperfusion. Urine was obtained through a catheter during the experiment at baseline, after coronary occlusion, at reperfusion, and between 1 and 2 hours after reperfusion.
Clinical Studies
Volunteers and patients were enrolled at the Mater Hospital (Dublin, Ireland) and at the Center for Experimental Therapeutics, University of Pennsylvania (Philadelphia). Three studies were performed. In the first, the urinary excretion of 8-epi PGF2 was characterized in normal volunteers. Twelve-hour urinary collections were obtained from 14 healthy control subjects and compared with "spot" samples taken at the beginning of the 12-hour collection from the same subjects. The diurnal variation of 8-epi PGF2 excretion was examined in 6 normal nonsmoking volunteers. Twelve-hour urinary collections were obtained on days 1, 3, and 7 in 7 healthy subjects to assess short-term variability in excretion.
The second study involved recruitment of 20 healthy volunteers (age, 40 to 89 years; 12 men and 8 women) and 20 patients with stable angina recruited from the Cardiovascular Medicine outpatient service. These patients (17 men and 3 women) were matched for age (range, 46 to 75 years), and all had angiographically proven coronary artery disease. Their symptoms were controlled on oral nitrates (n=17), ß-blockers (n=15), and calcium channel blockers (n=16). Seventeen of the patients were taking aspirin. The patient mix reflected the socioeconomic and ethnic backgrounds of the hospital catchment area; all were white, and social classes 3 through 5 predominated (n=18). All patients either were nonsmokers or had abstained from cigarette smoking for at least 2 years. Twelve patients presenting with classic symptoms of myocardial infarction who received streptokinase (n=10) or rt-PA (n=2) were also studied (age range, 52 to 70 years; 8 men and 4 women). All had subsequent confirmation of the diagnosis by both ECG and enzyme changes. Urinary 8-epi PGF2 was again measured in free flow spot urines in patients with myocardial infarction. These were the first samples obtained after the administration of either streptokinase (n=10) or rt-PA (n=2). Samples were collected from 1 patient before and in serial collections of urine after administration of streptokinase. All the patients with myocardial infarction also received aspirin immediately on diagnosis and an intravenous heparin infusion 6 hours after completion of thrombolytic therapy. There were no significant bleeding complications of therapy.
The third study was performed in 5 patients (age, 52 to 65 years; 4 men and 1 woman) undergoing CABG. Four were being treated with aspirin up to the time of surgery. Urine samples for analysis of 8-epi PGF2 were collected through a catheter, preoperatively, and before bypass in 15-minute aliquots during the revascularization procedure and subsequent aortic unclamping and at intervals of 30 minutes, 1 hour, and 24 hours postoperatively.
Measurement of LDL Oxidation
To address the relationship of 8-epi PGF2 generation with an index of free radical generation commonly used ex vivo or in vitro, we measured its formation during copper-induced oxidation of LDL. After an overnight fast, blood from healthy, normolipemic male volunteers (n=6) was collected, and LDL was prepared by sequential density gradient ultracentrifugation according to a previously described method.30 Protein concentration was determined by the Lowry method, with BSA used as standard.31 LDL was used at a final concentration of 0.4 mg of protein per milliliter. LDL was oxidized by use of CuCl2 (20 µmol/L) in PBS at 37°C. Samples were collected at 0, 3, 6, 9, and 24 hours for analysis.
The presence of lipid oxidation products on LDL was determined spectrophotometrically by measurement of TBARS levels monitored at 532 nm32 and by assessment of the lipid hydroperoxide generation by use of the FOX 2 assay monitoring at 560 nm.33 Total 8-epi PGF2 levels were measured as described below.
8-Epi PGF2 Analysis
Urinary and LDL 8-epi PGF2 was assayed by gas chromatography/mass spectrometry as previously described.11 Briefly, urine samples were collected in polyethylene bottles containing 0.1% of the antioxidant butylated hydroxyanisole. They were kept refrigerated during the collection period, after which they were immediately divided into aliquots and stored at -20°C. A known amount of the internal standard [18O2]-epi PGF2 was added to each sample. After solid-phase extraction, the sample was applied to a silica gel TLC plate in 25 µL methanol and developed with a mobile phase of 90% ethyl acetate, 10% methanol, and 0.1% acetic acid. Next, the pentafluorobenzyl ester derivative was applied to a second TLC plate in 25 µL ethyl acetate and developed with a mobile phase of 100% ethyl acetate. After incubation of the N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide derivative at 50°C for 24 hours, each sample was run on a Delsai 200/Automass 150 gas chromatography/mass spectrometer. Quantification was performed with peak area ratio (Fig 1
). Urinary creatinines were determined by a standardized automated colorimetric assay with a Beckman Synchron CX system. Samples were expressed as picomoles per millimole of creatinine.
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EPR Measurement
To relate 8-epi PGF2 formation in vivo more closely to generation of free radicals as detected ex vivo, we examined the production of radicals using spin trapping in two patients undergoing CABG. PBN was purchased from the OMRF Spin Trap Source. A 100-mmol/L PBN-KRP stock solution was prepared by dissolving PBN in a Krebs-Ringer phosphate buffer solution (120 mmol/L NaCl, 5 mmol/L KCl, 1.3 mmol/L MgSO4, and 10 mmol/L Na2HPO4, pH 7.4), which was deoxygenated by bubbling argon. Blood samples (5 mL) were withdrawn from two subjects undergoing CABG from a central venous catheter and mixed with 2 mL of 100 mmol/L PBN-KRP. The mixture was centrifuged at 3500g for 5 minutes at 4°C, and 4 mL of plasma supernatant was mixed with 2.0 mL of deoxygenated toluene in a glass tube. This was centrifuged further at 7000g for 10 minutes at 4°C before freezing at -80°C, thawing, and aspirating the toluene layer. This freeze-thaw step was repeated as necessary to separate the toluene layer from the plasma proteins.34 35
A fraction (2 mL) of this supernatant was concentrated to 0.4 mL under nitrogen gas flow and transferred to a 4-mm quart tube. EPR measurement was performed at -20°C with a Varian E-109 spectrometer (Varian Associates) at the following settings: gain, 2.0x104; microwave frequency, 9.2 gHz; modulation frequency, 100 kHz; microwave power, 20 mW; modulation amplitude, 0.2 mT; scan range, 10 mT; time constant, 0.25 second; and scan time, 8 minutes.
Statistical Analysis
Data were compared by a one-way ANOVA and, if significant differences occurred, by pairwise comparison with Bonferroni's correction. Nonparametric data were analyzed by the Kruskal-Wallis ANOVA and the Wilcoxon test, if appropriate. All data are expressed as mean±SEM, and differences were considered significant at P<.05.
Results
Spot urinary 8-epi PGF2 determination closely correlated (r=.99, P<.0001) with levels measured in subsequent 12-hour samples in healthy individuals (Fig 2). There was no diurnal variation in 8-epi PGF2 excretion evident under physiological circumstances. Urinary levels in three serial collections over a 24-hour period in six healthy subjects were 62.7±5.9, 60.1±4.2, and 64.3±5.3 pmol/mmol creatinine (mean±SEM), respectively. Furthermore, there was no significant difference between urinary 8-epi PGF2 excretion 3 (69.3±24.1 pmol/mmol creatinine) and 7 (68.5±21.1 pmol/mmol creatinine) days after the index collection (62.7±21.6 pmol/mmol creatinine) in seven healthy volunteers.
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The time course of LDL peroxidation in response to CuCl2 was assessed in samples from five normal volunteers (Fig 3). Total 8-epi PGF2 levels were 0.35±0.04, 1.14±0.09, 3.73±0.19, 5.66±0.31, and 8.55±0.34 ng/mg LDL protein at 0, 3, 6, 9, and 24 hours, respectively. In the same samples, TBARS levels rose from 0.59±0.08 to 0.95±0.23, 18.4±2.9, 38.8±3.4, and 48.0±2.7 nmol malondialdehyde/mg LDL protein, and hydroperoxide levels rose from 67.6±6.9 to 154.6±17.0, 381±21.8, 424±16.3, and 514±28.6 nmol/mg LDL protein. The values of all three indexes of LDL oxidation were closely correlated.
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) rose after exposure of LDL to copper and was closely correlated with malondialdehyde (TBARS, 
) and lipid hydroperoxides (
) in the LDL (n=5).
Urinary 8-epi PGF2 excretion increased at reperfusion in the canine model of coronary thrombolysis. Restoration of coronary blood flow after thrombolysis was documented by Doppler (Fig 4A). Levels of 8-epi PGF2 were 432.7±55.2 pmol/mmol creatinine at baseline compared with 437.2±56.4 pmol/mmol creatinine after occlusion and 553.8±64.7 pmol/mmol creatinine (P<.05) immediately after reperfusion. Excretion returned toward baseline 2 hours after reperfusion (493.2±59.3 pmol/mmol creatinine; Fig 4B).
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8-Epi PGF2 excretion was 91.5±11.8 pmol/mmol creatinine in healthy volunteers and did not differ significantly in patients with stable coronary heart disease (95.7±6.3 pmol/mmol). However, there was a marked increase (P<.001) in urinary 8-epi PGF2 excretion (265.8±40.8 pmol/mmol) in patients treated with thrombolytic drugs for acute myocardial infarction (Fig 5).
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Urinary 8-epi PGF2 excretion was measured before and after thrombolysis in four patients. Levels increased after thrombolysis (from 333 and 65 to 488 and 237 pmol/mmol creatinine, respectively) in two of these patients, and in the remaining two, levels were high before thrombolysis and remained elevated after therapy (454 and 273 to 381 and 254 pmol/mmol creatinine, respectively). A pretreatment specimen and serial 6-hour posttreatment specimens were obtained in one patient. Levels rose after lytic therapy and gradually dropped to baseline 3 days after treatment (Fig 6).
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8-Epi PGF2 generation increased during cardioplegia and increased further during myocardial reperfusion after aortic unclamping (Fig 7). Levels at baseline (113.2±11.8 pmol/mmol) remained unchanged after sternotomy (104.8±17.9 pmol/mmol) but rose to 248.2±86.3 pmol/mmol by 30 minutes into the revascularization procedure (while the aorta was cross clamped). They increased further to 332.2±82.6 pmol/mmol at 15 minutes after myocardial reperfusion (P<.05). Thereafter, 8-epi PGF2 excretion returned to baseline values, reaching 181.2±50.4 pmol/mmol at 30 minutes and 120.2±9.9 pmol/mmol at 24 hours after surgery.
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Spin adduct formation rose markedly in two of the patients who underwent CABG (Fig 8A). Although the temporal pattern of change in EPR signals differed between the patients, they were closely correlated with urinary 8-epi PGF2 in both cases (r=.64, P=.03). The alterations in EPR spectra in one of these patients are illustrated in Fig 8B.
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Discussion
F2-isoprostanes are free radical–catalyzed prostaglandin F2-isomers formed in situ from arachidonic acid esterified in the membrane phospholipid.8 They are cleaved out presumptively by a phospholipase(s) A2 and appear in plasma and urine. Recently, isomers of prostaglandins of the E and D series have been described, as have isoleukotrienes and isothromboxanes.36 37 38 8-Epi PGF2 is one of the more abundant F2-isoprostanes and has been ascribed biological activity. Unlike conjugated dienes or lipid hydroperoxides, 8-epi PGF2 represents a chemically stable end product of lipid peroxidation. Whether it actually functions as an autacoid in vivo is currently unclear, but it is possible that it acts as an incidental ligand at eicosanoid receptors or a receptor distinct from but closely related to that for thromboxane A2.10 39 40 It is noteworthy that in the canine model of coronary thrombolysis, a thromboxane A2/prostaglandin endoperoxide-receptor antagonist enhanced the effect of aspirin administration,41 suggesting that nonenzymatic products of arachidonic acid, such as 8-epi PGF2, may be important in mediating vasoconstriction in vivo.
Urinary determination of 8-epi PGF2 excretion may be a sensitive index of oxidant stress. Excretion is increased in an animal model of free radical injury,8 in humans after poisoning with acetaminophen and paraquat,42 and in long-term cigarette smokers,43 diverse settings in which free radical–mediated tissue injury is strongly implicated.44 45 We have also provided preliminary evidence in the last group that administration of vitamin C, which is deficient in smokers,46 depresses urinary 8-epi PGF2 excretion.43 8-Epi PGF2 may reflect lipid peroxidation in atherogenesis. For example, zymosan-stimulated human monocytes, coincubated in vitro with LDL, markedly augment 8-epi PGF2 formation.47 This increase is prevented by pretreatment of the monocytes with antioxidants. Peroxynitrite, a highly reactive oxidant formed by nitric oxide and superoxide, induces the formation of "total" F2-isoprostanes in lipoproteins in vitro.48 Consistent with these observations, we have detected 8-epi PGF2 in human atherosclerotic plaque.49
In the present study, we have demonstrated a strong correlation between traditional indexes of oxidant stress and 8-epi PGF2 generation in LDL particles oxidized by CuCl2 in vitro. Consistent with these observations, the increase in urinary 8-epi PGF2 during coronary reperfusion corresponded in both time and magnitude to changes in spin trapping of PBN adducts, as detected by EPR, in two patients ex vivo. There has been considerable speculation as to how ex vivo indexes such as the oxidizability of LDL might relate to actual lipid peroxidation in vivo. These observations suggest that measurement of isoprostanes promises to elucidate the nature of this relationship.
The source of 8-epi PGF2 in urine is likely to be conditional on the experimental setting or the disease under study, as is the case with conventional prostaglandins.50 However, we assume that urinary 8-epi PGF2 is likely to reflect oxidant stress in tissues other than the kidney. Thus, although studies of the formal disposition of 8-epi PGF2 in humans have not been reported, both plasma and urinary 8-epi PGF2 are elevated in liver cirrhosis,51 and both plasma and urinary levels of "total" F2-isoprostanes are elevated in smokers,52 two syndromes of extrarenal oxidant stress. Studies in the rat suggest that the liver plays a minor role in the biotransformation of F2-isoprostanes.8
A major limitation of the study of oxidant injury in cardiovascular disease has been the imprecision of analytical indexes of the process in vivo and the use of ex vivo methodology that is of arguable relevance to what is actually occurring in vivo. The absence of such indexes has limited the ability to define appropriate doses and dosing intervals for antioxidants and to provide a rational basis for the clinical evaluation of such compounds. The present study provides the first evidence of oxidant stress in the clinical setting of coronary reperfusion, using the noninvasive measurement of an isoprostane. Urinary 8-epi PGF2 is increased in patients with myocardial infarction who are treated with thrombolytic drugs and after clamp release in patients undergoing CABG. We have also simulated the lysis-related increase observed in humans in an animal model of thrombosis and thrombolysis. In this setting, urinary 8-epi PGF2 does not increase with circumflex coronary thrombosis but rises significantly on reperfusion with rt-PA. Preliminary evidence suggests that 8-epi PGF2 may also be increased in some patients presenting with myocardial infarction before the administration of the thrombolytic drug. However, levels are not elevated in patients with stable coronary artery disease. Interestingly, we have also recently observed an increase in urinary 8-epi PGF2 after carotid reperfusion in patients undergoing endarterectomy49 and in patients undergoing angioplasty.53
Our findings are of potential relevance to the modulation of reperfusion injury. First, the observations in patients suggest that there is a rational basis for evaluating antioxidants as therapy adjuvant to thrombolytic drugs. Second, the availability of an animal model of thrombolysis that simulates biochemically what is observed in patients offers a convenient setting in which to evaluate antioxidant drugs. Finally, such a quantitative index of oxidant stress would provide a basis for rational dose finding with such agents. Although the assay described here is too cumbersome for large-scale application in clinical trials, we have used gas chromatography/mass spectrometry to validate immunoassays for 8-epi PGF2.54 The development of specific and more trivial assays for other isoprostanes is likely to broaden the applicability of this approach.
The predominant pathway for 8-epi PGF2 formation in vivo is through free radical–catalyzed transformation of arachidonic acid. However, we have shown that 8-epi PGF2, unlike other F2 isoprostanes, is also a minor product of COX-1 in activated human platelets11 and of cyclooxygenase-2 in monocytes.47 Many clinical syndromes in which free radicals have been implicated are associated with platelet activation. For example, we have demonstrated that urinary thromboxane metabolites are elevated in both chronic cigarette smokers and in patients reperfused with thrombolytic drugs,55 56 reflecting platelet activation in vivo.57 Elevations in urinary 8-epi PGF2 were observed in the present study, despite treatment of most of the patients with myocardial infarction (17 of 20) and those undergoing elective CABG (4 of 5) with aspirin. Future studies will determine whether aspirin may have concealed an even more pronounced increase in the biosynthesis of this compound. However, a formal evaluation in chronic cigarette smokers, a setting of modest COX-1 activation compared with thrombolysis, suggests that the COX-1 pathway is a trivial contributor to overall 8-epi PGF2 biosynthesis, as reflected by its excretion in urine.43
In summary, coronary reperfusion is associated with an increase in urinary 8-epi PGF2, which is likely to reflect oxidant stress in vivo. Our data suggest a rational basis for dose finding with antioxidant drugs and their evaluation in patients receiving thrombolytic therapy or undergoing elective CABG. Measurement of isoeicosanoids and other approaches to estimating oxidant stress in vivo44 may resolve the controversial role of free radicals in clinical syndromes of reperfusion injury.58 59
Selected Abbreviations and Acronyms
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Acknowledgments
This work was supported by grants (G.A.F.) from the Wellcome Trust and the NIH (MOIRR00040 and HL-54500) and research fellowships from the Wellcome Trust (N.D.), the Health Research Board of Ireland (M.P.R.), and the Irish Heart Foundation (N.D. and M.P.R.). We are indebted to Peader McGinn, PhD, of the Mater Hospital for his technical assistance and to Andy Cucchiara, PhD, of the University of Pennsylvania for his help with the statistical analysis of the data.
Received October 10, 1996; revision received December 5, 1996; accepted December 16, 1996.
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