Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tg(sm/p22phox) ...mice, which overexpress the NADPH oxidase subunit p22(phox) in smooth muscle, and mice with vascular-specific deletion of extracellular SOD) and have shown that these animals develop vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension with age. T cells from tg(sm/p22phox) mice produced high levels of IL-17A and IFN-γ. Crossing tg(sm/p22phox) mice with lymphocyte-deficient Rag1(-/-) mice eliminated vascular inflammation, aortic stiffening, renal dysfunction, and hypertension; however, adoptive transfer of T cells restored these processes. Isoketal-protein adducts, which are immunogenic, were increased in aortas, DCs, and macrophages of tg(sm/p22phox) mice. Autologous pulsing with tg(sm/p22phox) aortic homogenates promoted DCs of tg(sm/p22phox) mice to stimulate T cell proliferation and production of IFN-γ, IL-17A, and TNF-α. Treatment with the superoxide scavenger tempol or the isoketal scavenger 2-hydroxybenzylamine (2-HOBA) normalized blood pressure; prevented vascular inflammation, aortic stiffening, and hypertension; and prevented DC and T cell activation. Moreover, in human aortas, the aortic content of isoketal adducts correlated with fibrosis and inflammation severity. Together, these results define a pathway linking vascular oxidant stress to immune activation and aortic stiffening and provide insight into the systemic inflammation encountered in common vascular diseases.
The isoprostanes—25 years later Milne, Ginger L.; Dai, Qi; Roberts, L. Jackson
Biochimica et biophysica acta,
04/2015, Letnik:
1851, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Isoprostanes (IsoPs) are prostaglandin-like molecules generated independent of the cyclooxygenase (COX) by the free radical-induced peroxidation of arachidonic acid. The first isoprostane species ...discovered were isomeric to prostaglandin F2α and were thus termed F2-IsoPs. Since the initial discovery of the F2-IsoPs, IsoPs with differing ring structures have been identified as well as IsoPs from different polyunsaturated fatty acids, including eicosapentaenoic acid and docosahexanenoic acid. The discovery of these molecules in vivo in humans has been a major contribution to the field of lipid oxidation and free radical research over the course of the past 25 years. These molecules have been determined to be both biomarkers and mediators of oxidative stress in numerous disease settings. This review focuses on recent developments in the field with an emphasis on clinical research. Special focus is given to the use of IsoPs as biomarkers in obesity, ischemia-reperfusion injury, the central nervous system, cancer, and genetic disorders. Additionally, attention is paid to diet and lifestyle factors that can affect endogenous levels of IsoPs. This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: analysis and biological relevance.”
•Isoprostanes (IsoPs) are formed from the free radical oxidation of arachidonic acid.•IsoPs are biomarkers of oxidative stress in human disease.•When quantifying IsoPs it is important to consider their formation and metabolism.•IsoPs are biologically active and can mediate the pathophysiology of disease.
The purpose of this position paper is to present a critical analysis of the challenges and limitations of the most widely used fluorescent probes for detecting and measuring reactive oxygen and ...nitrogen species. Where feasible, we have made recommendations for the use of alternate probes and appropriate analytical techniques that measure the specific products formed from the reactions between fluorescent probes and reactive oxygen and nitrogen species. We have proposed guidelines that will help present and future researchers with regard to the optimal use of selected fluorescent probes and interpretation of results.
Coronary heart disease (CHD) is the leading single cause of death in the United States and most Western countries, killing more than 400,000 Americans per year. Although CHD often manifests suddenly ...as a fatal myocardial infarction, the atherosclerosis that gives rise to the infarction develops gradually and can be markedly slowed or even reversed through pharmacological and lifestyle interventions. These same atherosclerotic processes also drive related vascular diseases such as stroke and peripheral artery disease, and individuals surviving occlusive events often develop additional complications including ischemic cardiomyopathy and heart failure. Therefore, better detection of subclinical atherosclerosis, along with more effective treatments, could significantly reduce the rate of death from CHD and related vascular diseases in the United States. In recent years, oxidation of polyunsaturated fatty acids (PUFAs) in plasma lipoproteins has been postulated to be a critical step in the development of atherosclerosis. If so, then monitoring lipid peroxidation should be a useful indicator of disease risk and progression. This review focuses on the evidence that specific PUFA peroxidation products, the F2-isoprostanes, are useful biomarkers that could potentially be utilized as indicators of CHD.
Rhabdomyolysis-induced renal failure represents up to 15% of all cases of acute renal failure. Many studies over the past 4 decades have demonstrated that accumulation of myoglobin in the kidney is ...central in the mechanism leading to kidney injury. However, some discussion exists regarding the mechanism mediating this oxidant injury. Although the free-iron-catalyzed Fenton reaction has been proposed to explain the tissue injury, more recent evidence strongly suggests that the main cause of oxidant injury is myoglobin redox cycling and generation of oxidized lipids. These molecules can propagate tissue injury and cause renal vasoconstriction, two of the three main conditions associated with acute renal failure. This review presents the evidence supporting the two mechanisms of oxidative injury, describes the central role of myoglobin redox cycling in the pathology of renal failure associated with rhabdomyolysis, and discusses the value of therapeutic interventions aiming at inhibiting myoglobin redox cycling for the treatment of rhabdomyolysis-induced renal failure.
Free radicals and oxidants are now implicated in physiological responses and in several diseases. Given the wide range of expertise of free radical researchers, application of the greater ...understanding of chemistry has not been uniformly applied to biological studies. We suggest that some widely used methodologies and terminologies hamper progress and need to be addressed. We make the case for abandonment and judicious use of several methods and terms and suggest practical and viable alternatives. These changes are suggested in four areas: use of fluorescent dyes to identify and quantify reactive species, methods for measurement of lipid peroxidation in complex biological systems, claims of antioxidants as radical scavengers, and use of the terms for reactive species.
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•Dye oxidation alone is insufficient evidence for detection of reactive species in biology.•Nonenzymatic lipid peroxidation assessment requires product analysis by mass spectroscopy.•Antioxidant claims require quantitative dose–response lowering of oxidative stress.•“ROS” and “RNS” should be used only when defined and the actual species are unknown.
We examine the weakening of the Atlantic Meridional Overturning Circulation (AMOC) in response to increasing CO
2
at different horizontal resolutions in a state-of-the-art climate model and in a ...small ensemble of models with differing resolutions. There is a strong influence of the ocean mean state on the AMOC weakening: models with a more saline western subpolar gyre have a greater formation of deep water there. This makes the AMOC more susceptible to weakening from an increase in CO
2
since weakening ocean heat transports weaken the contrast between ocean and atmospheric temperatures and hence weaken the buoyancy loss. In models with a greater proportion of deep water formation further north (in the Greenland-Iceland-Norwegian basin), deep-water formation can be maintained by shifting further north to where there is a greater ocean-atmosphere temperature contrast. We show that ocean horizontal resolution can have an impact on the mean state, and hence AMOC weakening. In the models examined, those with higher resolutions tend to have a more westerly location of the North Atlantic Current and stronger subpolar gyre. This likely leads to a greater impact of the warm, saline subtropical Atlantic waters on the western subpolar gyre resulting in greater dense water formation there. Although there is some improvement of the higher resolution models over the lower resolution models in terms of the mean state, both still have biases and it is not clear which biases are the most important for influencing the AMOC strength and response to increasing CO
2
.
Oxidative stress, characterized by an imbalance between increased exposure to free radicals and antioxidant defenses, is a prominent feature of many acute and chronic diseases and even the normal ...aging process. However, definitive evidence for this association has often been lacking due to recognized shortcomings with methods previously available to assess oxidant stress status in vivo in humans. Several in vitro markers of oxidative stress are available, but most are of limited value in vivo because thay lack sensitivity and/or specificity or require invasive methods. Isoprostanes (IsoPs) are prostaglandin (PG)-like compounds that are produced in vivo independently of cyclooxygenase enzymes, primarily by free radical-induced peroxidation of arachidonic acid. F2-IsoPs are a group of 64 compounds isomeric in structure to cyclooxygenase- derived PGF2α. Other products of the IsoP pathway are also formed in vivo by rearrangement of labile PGH2-like IsoP intermediates including E2- and D2-IsoPs, cyclopentenone-A2- and J2-IsoPs, and highly reactive acyclicketoaldehydes (isoketals). Oxidation of docosahexaenoic acid, an abundant unsaturated fatty acid in the central nervous system, results in the formation of IsoP-like compounds, termed neuroprostanes. Measurement of F2-IsoPs is the most reliable approach to assess oxidative stress status in vivo, providing an important tool to explore the role of oxidative stress in the pathogenesis of human disease. Moreover, F2-IsoPs and other products of the IsoP pathway exert potent biological actions both via receptor-dependent and independent mechanisms and therefore may be pathophysiological mediators of disease. Measurement of F2-IsoPs may provide a uniquely valuable approach to understanding of the clinical pharmacology of antioxidants.
The goal was to reduce adverse pulmonary adverse outcomes, oxidative stress, and inflammation in neonates of 24 to 28 weeks of gestation initially resuscitated with fractions of inspired oxygen of ...30% or 90%.
Randomized assignment to receive 30% (N = 37) or 90% (N = 41) oxygen was performed. Targeted oxygen saturation values were 75% at 5 minutes and 85% at 10 minutes. Blood oxidized glutathione (GSSG)/reduced glutathione ratio and urinary o-tyrosine, 8-oxo-dihydroxyguanosine, and isoprostane levels, isofuran elimination, and plasma interleukin 8 and tumor necrosis factor alpha levels were determined.
The low-oxygen group needed fewer days of oxygen supplementation (6 vs 22 days; P < .01) and fewer days of mechanical ventilation (13 vs 27 days; P < .01) and had a lower incidence of bronchopulmonary dysplasia at discharge (15.4% vs 31.7%; P < .05). GSSG/reduced glutathione x 100 ratios at day 1 and 3 were significantly higher in the high-oxygen group (day 1: high-oxygen group: 13.36 +/- 5.25; low-oxygen group: 8.46 +/- 3.87; P < .01; day 3: high-oxygen group: 8.87 +/- 4.40; low-oxygen group: 6.97 +/- 3.11; P < .05). Urinary markers of oxidative stress were increased significantly in the high-oxygen group, compared with the low-oxygen group, in the first week after birth. GSSG levels on day 3 and urinary isofuran, o-tyrosine, and 8-hydroxy-2'-deoxyguanosine levels on day 7 were correlated significantly with development of chronic lung disease.
Resuscitation of preterm neonates with 30% oxygen causes less oxidative stress, inflammation, need for oxygen, and risk of bronchopulmonary dysplasia.
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