8-epi-prostaglandin-f2alpha and Arteriosclerosis

Postaglandins(PG) and low-density lipoproteins (LDL) both are playing a key role in atherogenesis. Their interaction at the local vascular level is of central relevance in plaque formation and progression. Details of these complex actions however, still need to be elucidated. Lipoproteins are influencing the PG-production of arterial wall cells and platelets, while PGs in turn have been shown to regulate lipoprotein receptor binding and entry into the arterial wall. Modification of LDL severely influences arterial wall trapping and foam cell formation. During LDL-modification, isoprostanes, a new family of compounds generated by free radical catalysed action, independent of cyclooxygenase, are formed. 8-epi PGF(2alpha) the most well known member exerts a great variety of proatherogenic actions, among them vasoconstriction and platelet activation; it also serves as a mitogen and stimulator of endothelin release. The influence of various eicosanoids on lipoprotein modification, however, has not been assessed yet.

Topics: Arteriosclerosis; Dinoprost; Epoprostenol; Humans; Lipid Peroxidation; Lipoproteins, LDL; Prostaglandins E; Prostaglandins F

Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between hyperglycemia and the development of complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that oxidative stress may play a key role in the etiology of diabetic complications. 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-PGF(2alpha) has been described in association with both type 1 and type 2 diabetes mellitus, and correlates with impaired glycemic control. Besides providing a likely noninvasive index of lipid peroxidation in this setting, measurements of specific F(2) 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-PGF(2alpha) in vitro suggest that it and other isoeicosanoids may modulate the functional consequences of lipid peroxidation in diabetes, evidence that this is likely in vivo remains inadequate at this time.

Topics: Animals; Antioxidants; Arachidonic Acids; Arteriosclerosis; Biomarkers; Coronary Disease; Diabetes Complications; Diabetes Mellitus; Dietary Supplements; Dinoprost; F2-Isoprostanes; Humans; Hyperglycemia; Lipid Peroxidation; Oxidative Stress; Protein Isoforms; Vitamin E

F2-isoprostanes are prostaglandin F2-like compounds being formed by non-enzymatic peroxidation of arachidonic acid in vivo. They have a variety of biological actions. The most important compound of this group is 8-epi-PGF(2 alpha) being capable to induce vasconstriction in particular of lung- and renal vascular tissue. Isoprostanes are present in esterified form; in free form they become available after hydrolysis by phospholipase A. An increase in isoprostanes is an important indicator of oxidative stress in-vivo due to a variety of different noxi such as metal- or non-metal ions for cigarette smoke. Isoprostanes show an activation of platelets; as a consequence of the interaction of 8-epi-PGF(2 alpha) with specific receptors platelet aggregation may be induced or may be enhanced together with other agonists. Due to these preliminary results isoprostanes could become an interesting substance in angiology in the future for diagnosis of oxidative stress as well as in the understanding of the pathogenesis of atherosclerosis.

Topics: Animals; Arteriosclerosis; Dinoprost; Humans; Lipid Peroxidation; Platelet Aggregation; Vasoconstriction

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 alpha 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 alpha 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.

Topics: Antioxidants; Arteriosclerosis; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Dinoprost; F2-Isoprostanes; Free Radicals; Gas Chromatography-Mass Spectrometry; Humans; Hyperlipidemias; Immunoassay; Indicator Dilution Techniques; Lipid Peroxidation; Oxidative Stress; Platelet Aggregation; Prostaglandins F; Risk Factors; Thrombosis; Vasoconstrictor Agents

Cigarette smoking, a key risk factor for the development of vascular disease, is associated with an increased 8-epi-prostaglandin (PG) F(2alpha). Elevated 8-epi-PGF(2alpha) has been found in vascular tissue, blood and urine as well. We examined the influence of quitting cigarette smoking in 71 patients (38 males, 33 females; aged 32-67 a) with clinically manifested atherosclerosis and various risk factors. In addition, in eight patients with hypercholesterolemia without clinical manifestation of atherosclerosis quitting smoking was monitored as well. Twenty-six of the patients with manifested atherosclerosis and five with hypercholesterolemia restarted and the isoprostanes in plasma, serum and urine were monitored in these patients as well. Quitting cigarette smoking induces an immediate decline becoming significant after 1 or 2 weeks. Restarting smoking results in an increase in 8-epi-PGF(2alpha) reaching prevalues within almost 1 week. These findings indicate that the in vivo oxidation injury associated with cigarette smoking quickly decreases after quitting but increases soon after restarting immediately.

Topics: Adult; Aged; Arteriosclerosis; Biomarkers; Diabetes Complications; Diabetes Mellitus; Dinoprost; F2-Isoprostanes; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Risk Factors; Smoking; Smoking Cessation; Time Factors

The formation of prostacyclin (PGI(2)), thromboxane (TX) A(2), and isoprostanes is markedly enhanced in atherosclerosis. We examined the relative contribution of cyclooxygenase (COX)-1 and -2 to the generation of these eicosanoids in patients with atherosclerosis.. The study population consisted of 42 patients with atherosclerosis who were undergoing surgical revascularization. COX-2 mRNA was detected in areas of atherosclerosis but not in normal blood vessel walls, and there was evidence of COX-1 induction. The use of immunohistochemical studies localized the COX-2 to proliferating vascular smooth muscle cells and macrophages. Twenty-four patients who did not previously receive aspirin were randomized to receive either no treatment or nimesulide at 24 hours before surgery and then for 3 days. Eighteen patients who were receiving aspirin were continued on a protocol of either aspirin alone or a combination of aspirin and nimesulide. Urinary levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha), metabolites of TXA(2) and PGI(2), respectively, were elevated in patients with atherosclerosis compared with normal subjects (3211+/-533 versus 679+/-63 pg/mg creatinine, P<0.001; 594+/-156 versus 130+/-22 pg/mg creatinine, P<0.05, respectively), as was the level of the isoprostane 8-iso-PGF(2alpha). Nimesulide reduced 2, 3-dinor-6-keto-PGF(1alpha) excretion by 46+/-5% (378.3+/-103 to 167+/-37 pg/mg creatinine, P<0.01) preoperatively and blunted the increase after surgery. Nimesulide had no significant effect on 11-dehydro-TXB(2) before (2678+/-694 to 2110+/-282 pg/mg creatinine) or after surgery. The levels of both products were lower in patients who were taking aspirin, and no further reduction was seen with the addition of nimesulide. None of the treatments influenced urinary 8-iso-PGF(2alpha) excretion.. Both COX-1 and -2 are expressed and contribute to the increase in PGI(2) in patients with atherosclerosis, whereas TXA(2) is generated by COX-1.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arteriosclerosis; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Epoprostenol; F2-Isoprostanes; Female; Humans; Isoenzymes; Macrophages; Male; Membrane Proteins; Microscopy, Fluorescence; Muscle, Smooth, Vascular; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Thromboxane A2; Thromboxane B2

Recent years have seen increased numbers of children with conditions that contribute strongly to atherosclerotic disease, such as passive smoking, obesity, and dyslipidemia. In the present study, we evaluated the utility of non-invasive urinary markers in preventing lifestyle-related diseases by comparing lipid metabolism-related parameters with oxidative stress markers in school children.. Subjects were 85 first-grade students. The variables examined included the smoking in subjects' household; exercise habits; height and weight; blood pressure; and plasma total cholesterol, high-density lipoprotein cholesterol, triglyceride, leptin, blood sugar, urinary cotinine, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and 8-isoprostaglandin F2α (IsoP).. Of the subjects, 10.6% were obese (% overweight ≥ 20%), 3.5% had a high-risk arteriosclerosis index (AI; 3 ≤ AI < 5), and 29.4% were passive smokers. No significant differences were seen between boys and girls for any of the measurement parameters. Both urinary 8-OHdG (6.8-24.5 ng/mg creatinine) and IsoP (0.9-7.4 ng/mg creatinine) were detected in all subjects, and a significant positive correlation was seen between the two markers. On multiple regression analysis using AI as an objective variable and all non-invasive markers as explanatory variables, urinary IsoP correlated most strongly with AI (P ≤ 0.01).. Risk factors for atherosclerosis in adults, such as obesity and hypercholesterolemia, are associated with oxidative stress and inflammation. The present findings of the strongest correlation between urinary IsoP and AI suggest that urinary IsoP may serve as a non-invasive and effective early marker in predicting risk in children of developing lifestyle-related diseases.

Topics: Arteriosclerosis; Biomarkers; Child; Dinoprost; Dyslipidemias; Female; Humans; Incidence; Japan; Lipids; Male; Overweight; Oxidative Stress; Risk Assessment; Risk Factors; Schools

Alterations in the elastic behavior of arteries is an early sign of vascular damage in atherogenesis and may be promoted by oxidative stress (OxS). However, studies designed for simultaneous assessment of arterial elasticity and OxS status in patients with peripheral arterial disease (PAD) are absent. The purpose of this study was to assess large (C1) and small artery elasticity (C2) and indices of OxS in patients with PAD as well as to investigate possible relationships between these parameters.. Arterial elasticity was assessed noninvasively by pulse wave analysis (PWA) and biochemical measurements were taken from 38 patients with PAD and from 28 matched control subjects. The elasticity indices of the arteries were derived from PWA based on the modified Windkessel model and the OxS status was measured using urinary 8-iso-prostaglandin F2alpha (F2-IsoPs) and plasma baseline diene conjugates of low-density lipoproteins (LDL-BDC).. Patients with PAD showed significantly reduced C1 and C2 and increased values of F2-IsoPs and LDL-BDC. There was an inverse association between C1 and F2-IsoPs, as well as between C2 and F2-IsoPs (R=-.3, P=.04; R=-.49, P=.002, respectively) in the patient group, but not in the controls. After controlling for potential confounders in a multiple regression model, the associations between C2 and F2-IsoPs remained significant in the patient group (P<.001).. The possible link between arterial elasticity and F2-IsoPs in patients with PAD suggests that oxidative modifications may be involved in alterations of arterial elastic properties in atherosclerosis.

Topics: Aged; Arteries; Arteriosclerosis; Biomarkers; Blood Glucose; Blood Pressure; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Dinoprost; Elasticity; Heart Rate; Humans; Intermittent Claudication; Linear Models; Lower Extremity; Male; Middle Aged; Oxidative Stress; Peripheral Vascular Diseases; Severity of Illness Index; Triglycerides

Apolipoprotein A-II (apoA-II), the second major high-density lipoprotein (HDL) apolipoprotein, has been linked to familial combined hyperlipidemia. Human apoA-II transgenic mice constitute an animal model for this proatherogenic disease. We studied the ability of human apoA-II transgenic mice HDL to protect against oxidative modification of apoB-containing lipoproteins. When challenged with an atherogenic diet, antigens related to low-density lipoprotein (LDL) oxidation were markedly increased in the aorta of 11.1 transgenic mice (high human apoA-II expressor). HDL from control mice and 11.1 transgenic mice were coincubated with autologous very LDL (VLDL) or LDL, or with human LDL under oxidative conditions. The degree of oxidative modification of apoB lipoproteins was then evaluated by measuring relative electrophoretic mobility, dichlorofluorescein fluorescence, 9- and 13-hydroxyoctadecadienoic acid content, and conjugated diene kinetics. In all these different approaches, and in contrast to control mice, HDL from 11.1 transgenic mice failed to protect LDL from oxidative modification. A decreased content of apoA-I, paraoxonase (PON1), and platelet-activated factor acetyl-hydrolase activities was found in HDL of 11.1 transgenic mice. Liver gene expression of these HDL-associated proteins did not differ from that of control mice. In contrast, incubation of isolated human apoA-II with control mouse plasma at 37 degrees C decreased PON1 activity and displaced the enzyme from HDL. Thus, overexpression of human apoA-II in mice impairs the ability of HDL to protect apoB-containing lipoproteins from oxidation. Further, the displacement of PON1 by apoA-II could explain in part why PON1 is mostly found in HDL particles with apoA-I and without apoA-II, as well as the poor antiatherogenic properties of apoA-II-rich HDL.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Aorta; Aortic Diseases; Apolipoprotein A-I; Apolipoprotein A-II; Arteriosclerosis; Aryldialkylphosphatase; Cholesterol, HDL; Diet, Atherogenic; Dinoprost; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Hyperlipoproteinemia Type II; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Liver; Male; Mice; Mice, Transgenic; Oxidation-Reduction; Recombinant Fusion Proteins; Thiobarbituric Acid Reactive Substances

Circulating 8-iso-prostaglandin F 2alpha (8-iso-PGF 2alpha ) has been proposed as new indicator of oxidative stress, which is involved in the pathophysiologic changes of atherosclerosis. We proposed to test the hypothesis that 8-iso-PGF 2alpha is an independent predictor of symptomatic peripheral arterial disease (PAD).. A case-control study in 100 patients with symptomatic PAD and 100 control subjects matched for age, sex, and diabetes mellitus was conducted. Smokers and subjects using lipid-lowering drugs were excluded. Serum total 8-iso-PGF 2alpha was quantified with an enzyme immunoassay.. Median 8-iso-PGF 2alpha was higher in patients with PAD than in control subjects (63 vs 42 pg/mL; P = .001). Logistic regression with hypertension, body mass index, and creatinine, low-density lipoprotein (LDL) cholesterol, triglyceride, high-sensitivity C-reactive protein (hs-CRP), 8-iso-PGF 2alpha , and total homocysteine concentrations as independent variables and case-control status as dependent variable revealed significant odds ratios (OR) for hypertension (OR, 3.74; 95% confidence interval [CI], 1.85-7.53), low-density lipoprotein cholesterol (OR, 1.16, for an increment of 10 mg/dL; 95% CI, 1.07-1.27), high-sensitivity C-reactive protein (OR, 1.02, for an increment of 1 mg/L; 95% CI, 1.00-1.03), and 8-iso-PGF 2alpha (OR, 1.11, for an increment of 10 pg/mL; 95% CI, 1.03-1.20).. Serum total 8-iso-PGF 2alpha was an independent predictor of PAD in the population studied. This finding supports the hypothesis that 8-iso-PGF 2alpha is a risk marker for PAD. Our results indicate increased systemic oxidative stress in patients with PAD.

Topics: Aged; Aged, 80 and over; Arteriosclerosis; Biomarkers; Case-Control Studies; Dinoprost; Female; Humans; Male; Middle Aged; Oxidative Stress; Peripheral Vascular Diseases; Predictive Value of Tests

Diet and exercise can affect blood pressure and atherosclerotic risk.. The present study was designed to examine the effects of a short-term, rigorous diet and exercise intervention on blood pressure, hyperinsulinemia, and nitric oxide (NO) availability. Men (n=11) were placed on a low-fat, high-fiber diet combined with daily exercise for 45 to 60 minutes for 3 weeks. Pre- and post fasting blood was drawn for serum lipid, insulin, 8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)), and glucose measurements. Anthropometric parameters, blood pressure (BP), and 24-hour urinary NO metabolite excretion (NO(X)), a marker of NO bioavailability, were measured. Systolic (P<0.01) and diastolic BP (P<0.01) and 8-iso-PGF(2alpha) decreased (P<0.05), whereas urinary NO(X) increased (P<0.05). There was a significant reduction in fasting insulin (P<0.01) and a significant correlation between the decrease in serum insulin and the increase in urinary NO(X) (r2=0.68, P<0.05). All fasting lipids decreased significantly, and the total cholesterol to high-density lipoprotein cholesterol ratio improved. Although body weight and body mass index (P<0.01) decreased, obesity was still present and there were no correlations between the change in body mass index and the change in insulin, BP, or urinary NO(X).. This intervention resulted in dramatic improvements in BP, oxidative stress, NO availability, and the metabolic profile within 3 weeks, mitigating the risk for atherosclerosis progression and its clinical sequelae.

Topics: Adult; Aged; Arteriosclerosis; Blood Pressure; Body Mass Index; Body Weight; Combined Modality Therapy; Dinoprost; Exercise; F2-Isoprostanes; Humans; Hypertension; Insulin; Male; Middle Aged; Nitric Oxide; Oxidative Stress

Diabetes mellitus (DM) is a well-established risk factor of cardiovascular diseases. We investigated the mechanism of the progression of arteriosclerosis in DM, focusing on the role of oxidative stress and insulin resistance in vivo. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an experimental model of type 2 DM, were assigned to 3 groups, based on supplementation with vitamin E (VE) or troglitazone (TR), a VE-derived agent which improves insulin-resistance. At 36 weeks, plasma and aortic tissue 8-iso-PGF2alpha contents, a vascular proliferating eicosanoid produced in vivo by oxidative stress, were measured by EIA. TGF-beta1 and TGF-beta1 receptor II were immunohistochemically analyzed. Histopathologically, medial area and the nuclear number of smooth muscle cells of the aorta were measured. The tissue 8-iso-PGF2alpha content (pg/g tissue) was significantly decreased by either VE or TR in the aorta (untreated-OLETF, 15,332+/-3,254 vs. TR-treated-OLETF, 7,092+/-1,992 or VE-treated-OLETF, 5,394+/-836, both p<0.01), but that in plasma decreased by only VE. VE and TR improved the increased the level of the actual medial area and the number of smooth muscle cells. The expression of TGF-beta1 was reduced, but TGF-beta1 receptor II was not. 8-iso-PGF2alpha may play an important role in the progression of arteriosclerosis. Antioxidant treatment may promise significant clinical benefits in the early diabetic stage.

Topics: Animals; Aorta; Arteriosclerosis; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Disease Progression; Eicosanoids; F2-Isoprostanes; Lipids; Male; Oxidative Stress; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Transforming Growth Factor beta1

The endothelial isoform of nitric oxide synthase (eNOS) has been considered to exert an antiatherosclerotic role through synthesis of NO. However, eNOS has been shown to generate superoxide, which could oxidize LDL and promote atherosclerosis. We sought to determine the role of eNOS in diet-induced fatty streak formation through the use of eNOS-deficient mice.. Mice were fed an atherogenic diet containing 15% fat, 1.25% cholesterol, and 0.5% sodium cholate for 12 weeks, and atherosclerotic lesions at the aortic root were measured after oil-red O staining. Unexpectedly, eNOS-deficient mice developed much smaller aortic lesions than did wild-type control mice (2544+/-1107 versus 7023+/-1569 microm2/section; P=0.03). This reduction in lesion formation could not be explained by changes in plasma levels of lipids and susceptibility of lipoproteins to oxidation. To examine whether eNOS contributed to the oxidation of LDL within the arterial wall, endothelial cells were isolated from the aorta of mice and incubated with native LDL in the absence or presence of N-Omega-nitro-L-arginine methyl ester (L-NAME), a specific NOS inhibitor. L-NAME significantly inhibited LDL oxidation by endothelial cells from wild-type animals (P<0.05), but it had no effect on LDL oxidation by endothelial cells from eNOS-deficient mice.. These data indicate that absence of eNOS-mediated LDL oxidation may contribute to the reduction of fatty-streak formation in eNOS-deficient mice.

Topics: Animals; Aortic Diseases; Arteriosclerosis; Cells, Cultured; Dinoprost; Endothelium, Vascular; Enzyme Inhibitors; F2-Isoprostanes; Female; Kinetics; Lipids; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Mice, Knockout; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III

PGI(2)and 8-epi-prostaglandin(PG)F(2 alpha)are antagonizing compounds. For both a key role in vascular pathology has been hypothesized. The isoprostane 8-epi-PGF(2 alpha)and the stable derivative of PGI(2), 6-oxo-PGF(1 alpha)were determined immunologically in the arterial wall of various species including humans. Human arterial tissue contained the highest amounts of 8-epi-PGF(2 alpha)and synthesized the lowest PGI(2). A significant negative correlation between 8-epi-PGF(2 alpha)and 6-oxo-PGF(1 alpha)was observed. Atherosclerotic segments showed significantly higher 8-epi-PGF(2 alpha)and lower 6-oxo-PGF(1 alpha). 8-epi-PGF(2 alpha)in the intima was higher than in the media, the highest amounts being found in foam-cell rich areas. Synthetic (activated) smooth muscle cells were associated with an enhanced 8-epi-PGF(2 alpha)as well as 6-oxo-PGF(1 alpha). Tissue samples derived from smokers contained more 8-epi-PGF(2 alpha)and produced less PGI(2). The by far highest 8-epi-PGF(2 alpha)/6-oxo-PGF(1 alpha)ratio was found in foam cell rich areas. Similar findings were obtained in rabbit and in minipig arteries. The total 8-epi-PGF(2 alpha)/6-oxo-PGF(1 alpha)ratio is low in normal tissue, increases significantly in an active atherosclerotic process and seems to be even further increased in an inactive atherosclerotic process. These findings are providing an information on the extent of oxidation injury at various sites of different types of atherosclerotic process.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aged, 80 and over; Animals; Arteries; Arteriosclerosis; Dinoprost; F2-Isoprostanes; Female; Foam Cells; Humans; Male; Middle Aged; Oxygen; Phenotype; Rabbits; Radioimmunoassay; Smoking

Isoprostanes are known as reliable markers of in vivo oxidation injury. Cigarette smoking has been shown to be associated with a significant increase in 8-epi-PGF(2alpha), a major member of this family of compounds. Quitting smoking reduces 8-epi-PGF(2alpha) values to normal within a couple of weeks only. In this follow-up we checked the 8-epi-PGF(2alpha), values in plasma, serum and urine in 28 people who restarted smoking after a quitting attempt of various duration. 8-epi-PGF(2alpha)shows a certain increase after restarting smoking reaching a maximum after already 1 week. Continuation of smoking does not significantly further increase 8-epi-PGF(2alpha). These data indicate a fast response of restarting as on quitting smoking on in vivo oxidation injury. The oxidation injury reflected by 8-epi-PGF(2alpha)may be a key pathogenetic mechanism in smoking-induced vascular injury.

Topics: Adult; Aged; Arteriosclerosis; Biomarkers; Dinoprost; F2-Isoprostanes; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Oxidative Stress; Smoking; Smoking Cessation; Time Factors

Lipoprotein peroxidation in the arterial wall has been implicated in atherogenesis. The superoxide radical is formed in arteries and can induce such oxidation. Extracellular superoxide dismutase (EC-SOD) occurs in high concentration in the vascular wall interstitium, and in this study, we examined the importance of the enzyme in atherogenesis. On an apolipoprotein E-null background, the limited aortic lesions induced by a 1-month atherogenic diet were larger in EC-SOD wild-type mice than in EC-SOD-null mice, whereas there were no differences between the EC-SOD genotypes in the larger lesions seen after 3 months on the diet or after 8 months on normal chow. Despite smaller or equal lesions in the EC-SOD-null mice, their cholesterol levels were somewhat higher. Also, on a wild-type background, there were no effects produced by the absence or presence of EC-SOD on atherogenic diet-induced aortic root lesions. The urinary excretion of the lipid peroxidation biomarker 8-isoprostaglandin F(2alpha) was related to the rates of atherogenesis in the mice but was not influenced by the EC-SOD genotype. Likewise, the EC-SOD status had no effect on the staining for oxidized low density lipoprotein epitopes in aortic root sections. Our findings suggest that EC-SOD has little influence on atherogenesis in mice.

Topics: Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Cholesterol; Diet, Atherogenic; Dinoprost; F2-Isoprostanes; Female; Lipoproteins, LDL; Male; Mice; Mice, Knockout; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Measurement of the F(2)-isoprostane, 8-epi-PGF(2alpha) is increasingly used as a sensitive and reliable marker of lipid peroxidation in vivo. Because the majority of 8-epi-PGF(2alpha) in plasma is associated with lipoproteins, it is possible that 8-epi-PGF(2alpha) derived from polyunsaturated fatty acid-rich food may become incorporated within these lipoproteins during synthesis and could contribute to the levels detected in plasma. In this study, we evaluated the postprandial effect of a single fast-food meal (McDonald's Big Mac meal, McDonald's Corp., London, England) on plasma total 8-epi-PGF(2alpha) in nine healthy subjects. Blood was collected before and 2 h postprandially. 8-Epi-PGF(2alpha) was measured by immunoaffinity extraction and gas chromatography-mass spectrometry. Fasting plasma 8-epi-PGF(2alpha) (875 +/- 25 pM) increased postprandially (956 +/- 23 pM, p <.05), although no significant change was observed in the normalized concentrations (2. 78 +/- 0.1 vs. 2.95 +/- 0.3 nmol/mmol arachidonic acid). Plasma lipid hydroperoxides, fatty acids, vitamin E, total antioxidant status, cholesterol, and triglycerides were not altered. Plasma glucose increased postmeal (4.4 +/- 0.1 vs. 4.9 +/- 0.1 mM, p <.05). These results indicate that the overall contribution of this lipid-rich meal to plasma 8-epi-PGF(2alpha) and other lipid peroxidation markers was small.

Topics: Adult; Antioxidants; Arachidonic Acid; Arteriosclerosis; Biomarkers; Dietary Fats; Dinoprost; Eating; F2-Isoprostanes; Female; Humans; Lipid Peroxidation; Male; Middle Aged

This study investigates how strenuous arm exercise affects oxidized-low density lipoprotein (O(X)-LDL) mediated-platelet activation in patients with SCI. Ten patients with SCI and ten age- and sex-matched healthy subjects exercised strenuously using an arm crank ergometer. The following measurements were taken both when the subjects were at rest, and immediately after exercise: plasma lipid profile, O(X)-LDL mediated platelet aggregability and [Ca(2+)]i, urinary 11-dehydro-thromboxane B2 (11-dehydro-TXB2) and 8-iso-prostaglandin F(2alpha), (8-iso-PG F(2alpha)) contents, and plasma NO metabolite (nitrite plus nitrate) level. Based on these measurements, the major findings of this study can be summarized as follows: 1) the SCI group had higher urinary 8-iso-PGF(2alpha) and 11-dehydro-TXB2 contents, but a lower plasma nitrite plus nitrate level than the control group; 2) at rest, the SCI group had a higher platelet aggregability and [Ca(2+)]i, and O(X)-LDL-potentiated platelet activation than the control group; 3) O(X)-LDL-potentiated platelet aggregation was enhanced by strenuous arm exercise in both groups, but the effect of exercise was more pronounced in the SCI group than in the control group; 4) treating the platelet with L-arginine inhibited O(X)-LDL-potentiated platelet activation in both groups. The study concludes that individuals with SCI had more extensive resting and exercise-enhanced O(X)-LDL-potentiated platelet activation and greater amounts of preformed lipid peroxides than those without SCI. Therefore, supplementation therapy with antioxidants may be needed for patients with SCI, especially in a strenuous arm exercise period.

Topics: Adult; Arm; Arteriosclerosis; Calcium; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Dinoprost; Exercise Test; F2-Isoprostanes; Female; Humans; Lipid Peroxidation; Lipoproteins, LDL; Male; Nitrates; Nitric Oxide; Nitrites; Oxidative Stress; Platelet Activation; Platelet Aggregation; Platelet Count; Risk Factors; Spinal Cord Injuries; Thromboxane B2

Isoprostanes (IP) have been identified as reliable markers of in vivo oxidation injury. Recently, in vascular tissue and blood as well as urine of cigarette smokers, increased IP values have been discovered. We examined 47 adults (26 males, 21 females; aged 30-66 years), admitted to a cardiovascular unit on an outpatient basis, with various risk factors but without any sign of manifestation of atherosclerosis. Refraining from cigarette smoking for a few days resulted in a significant drop of plasma, serum, and urinary 8-epi-PGF(2alpha). Thereafter, a further continuous decrease was monitored, reaching a steady state after about 4 weeks after quitting cigarette smoking. Prevalues of 8-epi-PGF(2alpha) were higher, depending on the type and number of risk factors; the decrease after quitting, however, was comparable. These results indicate that exsmokers may rapidly recover from their enhanced in vivo oxidation.

Topics: Adult; Aged; Arteriosclerosis; Biomarkers; Dinoprost; F2-Isoprostanes; Female; Humans; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Risk Factors; Smoking Cessation; Time Factors

Homocysteine is a risk factor for the development of atherosclerosis and its thrombotic complications. We have employed an animal model to explore the hypothesis that an increase in reactive oxygen species and a subsequent loss of nitric oxide bioactivity contribute to endothelial dysfunction in mild hyperhomocysteinemia. We examined endothelial function and in vivo oxidant burden in mice heterozygous for a deletion in the cystathionine beta-synthase (CBS) gene, by studying isolated, precontracted aortic rings and mesenteric arterioles in situ. CBS(-/+) mice demonstrated impaired acetylcholine-induced aortic relaxation and a paradoxical vasoconstriction of mesenteric microvessels in response to superfusion of methacholine and bradykinin. Cyclic GMP accumulation following acetylcholine treatment was also impaired in isolated aortic segments from CBS(-/+) mice, but aortic relaxation and mesenteric arteriolar dilation in response to sodium nitroprusside were similar to wild-type. Plasma levels of 8-epi-PGF(2alpha) (8-IP) were somewhat increased in CBS(-/+) mice, but liver levels of 8-IP and phospholipid hydroperoxides, another marker of oxidative stress, were normal. Aortic tissue from CBS(-/+) mice also demonstrated greater superoxide production and greater immunostaining for 3-nitrotyrosine, particularly on the endothelial surface. Importantly, endothelial dysfunction appears early in CBS(-/+) mice in the absence of structural arterial abnormalities. Hence, mild hyperhomocysteinemia due to reduced CBS expression impairs endothelium-dependent vasodilation, likely due to impaired nitric oxide bioactivity, and increased oxidative stress apparently contributes to inactivating nitric oxide in chronic, mild hyperhomocysteinemia.

Topics: Acetylcholine; Animals; Aorta; Arteriosclerosis; Cystathionine beta-Synthase; Dinoprost; Disease Models, Animal; Endothelium, Vascular; F2-Isoprostanes; Heterozygote; Humans; Hyperhomocysteinemia; In Vitro Techniques; Lipid Peroxides; Mice; Mice, Mutant Strains; Nitroprusside; Reactive Oxygen Species; Risk Factors; Thrombosis; Tyrosine; Vasodilation

Isoprostanes (IP) are a new family of compounds formed during oxidation injury. 8-epi-prostaglandin (PG) F2alpha, a vasoconstrictory and mitogenic substance, is increased in hyperlipidemia in blood and urine as well as at the vascular level in the intima, in particular along foam cells. Similarly, cigarette smoking is associated with an immediate increase in 8-epi-PGF2alpha and a quick drop after quitting. Also diabetes and even the more a combination of risk factors (for the development of atherosclerosis) results in increased 8-epi-PGF2alpha in various compartments. Others, such as sex, age, hypertension and obesity were of minor influence. These findings further indicate, that in-vivo oxidation injury as reflected by increased IP may play a relevant role in atherogenesis. IP may serve as useful markers to assess oxidation injury at a local level.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticholesteremic Agents; Arteriosclerosis; Blood Component Removal; Blood Vessels; Child; Child, Preschool; Dinoprost; Female; Humans; Hyperlipidemias; Immunohistochemistry; Lipoproteins, LDL; Male; Middle Aged; Molecular Structure; Smoking; Thiobarbituric Acid Reactive Substances; Vasoconstrictor Agents

This study's aim was to determine whether biochemical risk factors such as lipoprotein(a), fibrinogen, homocysteine, and insulin, as well as low-density lipoprotein (LDL) particle size, were predictive of carotid intimamedia thickness (IMT), an early marker of atherosclerosis, in subjects with familial hypercholesterolemia (FH). We also determined whether plasma 8-isoprostane, as a marker of in vivo lipid oxidation, correlated with carotid IMT. Twenty-two homozygous and 20 heterozygous subjects with FH were compared with 20 normocholesterolemic controls. On univariate analysis, plasma total and LDL cholesterol, the cholesterol-years score (CYS), lipoprotein(a), and fibrinogen, but not homocysteine or insulin, were positively related, and high-density lipoprotein (HDL) cholesterol was negatively related to carotid IMT. However, on multivariate analysis, only LDL cholesterol and the CYS predicted carotid IMT (multiple r = 0.82; r2 = 0.68; p <0.0001). The subjects with FH had large rather than small dense LDL particles, and plasma 8-isoprostane levels were not increased. LDL cholesterol and the CYS, or "cholesterol bulk" are the pivotal determinants of atherosclerosis and are the strongest predictors of carotid IMT in FH.

Topics: Adult; Arteriosclerosis; Carotid Stenosis; Cholesterol, LDL; Dinoprost; F2-Isoprostanes; Female; Heterozygote; Homozygote; Humans; Hyperlipoproteinemia Type II; Lipoprotein(a); Male; Risk Factors

Isoprostanes are a new family of compounds generated by the free radical catalyzed action on arachidonic acid. Formed during oxidation they have been claimed to be a reliable indicator of in vivo oxidation injury. We assessed the amount of 8-epi-PGF2alpha in human surgical specimens as compared to PGI2 (via its stable metabolite 6-oxo-PGF1alpha), the major compound generated by vascular tissue. 8-epi-PGF2alpha is low in normal vascular tissue as is the 8-epi-PGF2alpha/6-oxo-PGF1alpha ratio. The vessels of smokers in general exhibited an increased 8-epi-PGF2alpha (r=0.82) and a decreased 6-oxo-PGF1alpha (r=0.71). The 8-epi-PGF2alpha/6-oxo-PGF1alpha ratio is, not significantly, increased in vessels derived from hyperlipidemics and hypertensives. These findings indicate that lipid peroxidation occurs within the human arterial wall as evidenced by 8-epi-PGF2alpha, probably further decreasing the synthesis of PGI2 and promoting atherogenic mechanisms.

Topics: 6-Ketoprostaglandin F1 alpha; Age Factors; Aged; Arteriosclerosis; Blood Vessels; Dinoprost; Epoprostenol; F2-Isoprostanes; Female; Humans; Immunoassay; In Vitro Techniques; Male; Middle Aged

Accumulation of monocyte-derived foam cells in the arterial intima is a major event in the development of atherogenesis. We have examined whether native and oxidized lipoprotein(a) (Lp(a)) can induce adhesion of monocytic cells to aortic endothelium. The extensive oxidation of paired samples of Lp(a) and low-density lipoprotein (LDL) was achieved by O2.-/OH. free radicals produced by gamma radiolysis of water, leading to similar values for the formation of peroxidation markers (conjugated dienes, TBARS, 8-epi-PGF2alpha) for both Lp(a) and LDL. Rabbit aortic segments were incubated for 5 h in the presence of equimolar concentrations of native and oxidized preparations of Lp(a) and LDL (125 micromol cholesterol/l, corresponding to 40 and 30 mg protein/l for Lp(a) and LDL, respectively). The aortic segments were incubated with rhodamin-isothiocyanate labeled U937 monocytic cells for 30 min and cell adhesion was quantified by fluorescent microscopy. Native Lp(a), and to a larger extent oxidized Lp(a), significantly increased U937 cell adhesion by 2.3 and 2.7 fold compared to controls (P < 0.005 and P < 0.001, respectively). Monocytic cell adhesion was also increased by native LDL (1.6 fold, P < 0.005), and to a greater extent by oxidized LDL (2.3 fold, P < 0.001). Thus native Lp(a) enhances the adhesive properties of the arterial endothelium which may account for its proatherogenic action. Furthermore, our results show that oxidized Lp(a), as well as oxidized LDL, are potent stimuli of monocyte adhesion to endothelial cells.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Cell Adhesion; Dinoprost; Endothelium, Vascular; Free Radicals; Gamma Rays; Lipid Peroxidation; Lipoprotein(a); Lipoproteins, LDL; Male; Monocytes; Oxidation-Reduction; Rabbits; Thiobarbituric Acid Reactive Substances; Tumor Cells, Cultured

F2-Isoprostanes are prostaglandin (PG) isomers formed in situ in cell membranes by peroxidation of arachidonic acid. 8-epi PGF2alpha and IPF2alpha-I are F2-isoprostanes produced in humans which circulate in plasma and are excreted in urine. Measurement of F2-isoprostanes may offer a sensitive, specific, and noninvasive method for measuring oxidant stress in clinical settings where reactive oxygen species are putatively involved. We determined whether isoprostanes were present in human atherosclerotic lesions, where lipid peroxidation is thought to occur in vivo. 8-epi PGF2alpha ranged from 1.310-3.450 pmol/micromol phospholipid in atherectomy specimens compared with 0.045-0.115 pmol/micromol phospholipid (P < 0.001) in vascular tissue devoid of atherosclerosis. Corresponding values of IPF2alpha-I were 5.6-13.8 vs. 0.16-0.44 pmol/micromol phospholipid (P < 0.001). Levels of the two isoprostanes in vascular tissue were highly correlated (r = 0.80, P < 0.0001). Immunohistochemical studies confirmed that foam cells adjacent to the lipid necrotic core of the plaque were markedly positive for 8-epi PGF2alpha. These cells were also reactive with anti-CD68, an epitope specific for human monocyte/macrophages. 8-epi PGF2alpha immunoreactivity was also detected in cells positive for anti-alpha-smooth muscle actin antibody, which specifically recognizes vascular smooth muscle cells. Our results indicate that 8-epi PGF2alpha and IPF2alpha-I, two distinct F2-isoprostanes and markers of oxidative stress in vivo, are present in human atherosclerotic plaque. Quantitation of these chemically stable products of lipid peroxidation in target tissues, as well as in biological fluids, may aid in the rational development of antioxidant drugs in humans.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aorta; Arteries; Arteriosclerosis; Carotid Arteries; Dinoprost; Foam Cells; Humans; Isomerism; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Phospholipids; Pulmonary Artery

Oxidation of low-density lipoproteins (LDL) is well known to increase the atherogenic risk. Active smoking has been claimed to be associated with a significant oxidant stress determined by enhanced LDL oxidation and isoprostane formation. We assessed the susceptibility of LDL to oxidation in 9 healthy non-smokers and 7 smokers before and after three and five hours' exposure to passive smoking. Baseline values for the lag time, diene formation, malondialdehyde and isoprostanes differed in part significantly. In contrast to the data on active smoking, passive exposure to cigarette smoke did not significantly affect any of these parameters, nor diene formation and electrophoretic mobility in smokers and non-smokers alike. These results indicate that a single exposure to passive smoking does not induce relevant oxidation of LDL in men.

Topics: Adult; Arteriosclerosis; Dinoprost; F2-Isoprostanes; Female; Humans; Lipoproteins, LDL; Male; Malondialdehyde; Oxidation-Reduction; Risk Factors; Smoking; Tobacco Smoke Pollution