934 resultados para Oxidative Stress, NADPH Oxidases, endothelial NO Synthase
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Glukokortikoide (GCs) stellen wichtige Hormone in der Regulation der metabolischen Homostase dar. Synthetische GCs, wie Dexamethasone (DEX), spielen eine essentielle Rolle in der Behandlung inflammatorischer Krankheiten. Jedoch sind unter einer Dexamethason-Therapie zahlreiche Nebenwirkungen bekannt, so z.B. auch die Entwicklung einer Hypertonie, in deren Pathogenese oxidativer Stress eine entscheidende Rolle spielt. Obwohl sich in den vergangenen Jahren zahlreiche Studien zum Ziel setzten die GC-induzierte Hypertonie (GC-HT) aufzuklren, sind die genauen Mechanismen bis heute unklar. Eine erhhte Expression von NADPH Oxidasen (Nox) und eine Entkopplung der endothelialen NO Synthase (eNOS), die Hauptquellen reaktiver Sauerstoffspezies (ROS) im vaskulren System, tragen mageblich zur Pathogenese kardiovaskulrer Erkrankungen bei. Daher ist eine Beteiligung dieser Enzyme in GC-induziertem oxidativen Stress sehr wahrscheinlich. Folglich wurde die Hypothese aufgestellt, dass NADPH Oxidasen und eine entkoppelte eNOS die vielversprechendsten unter den zahlreichen involvierten pro- und anti-oxidativen Enzymen sind. Mit Fokus auf die oben genannten Systeme wurde in der vorliegenden Studie der Effekt von DEX mit Hilfe von in vivo (WKY Ratten) ebenso wie in vitro Experimenten (A7r5 und EA.hy 926 Zellen) untersucht. Dabei zeigte sich, dass Nox1, Nox4 und p22phox durch DEX unterschiedlich reguliert wurden. Nox1 wurde hoch-, Nox4 hingegen herunterreguliert, whrend p22phox unverndert blieb. Die Modufikation schien hierbei auf transkriptioneller und post-transkriptioneller Ebene stattzufinden. Durch die gegenstzliche Regulation von Nox1 und Nox4 bleibt die Nettowirkung der verschiedenen Nox Isoformen unklar. Immer mehr Studien bringen vaskulren oxidativen Stress mit der Pathogenese einer GC-HT in Zusammenhang, welche letztendlich zu einer verminderten Bioverfgbarkeit von Stickstoffmonoxid (NO) fhrt. Durch die eNOS produziertes NO stellt einen essentiellen Schutzfaktor der Blutgefe dar. Eine verminderte NO-Bioverfgbarkeit knnte die Folge einer eNOS-Entkopplung darstellen, ausgelst durch oxidativen Stress. Da die Verfgbarkeit von Tetrahydrobiopterin (BH4) entscheident ist fr die Aktivitt und enzymatische Kopplung der eNOS, beschftigt sich die vorliegende Arbeit mit GC-induzierten Vernderungen in der BH4-Versorgung. Die Behandlung von EA.hy 926 Zellen mit DEX fhrte zu einer zeit- und konzentrationsabhngigen Herunterregulation von eNOS auf mRNA- und Proteinebene. Gleichzeitig wurde die Phosphorylierung an Serine1177 vermindert. Als mageblicher Kopplungs-Schalter kann BH4 endogen ber zwei verschiedene Signalwege synthetisiert werden, welche durch die Enzyme GCH1 und DHFR reguliert werden. DEX fhrte zu einer zeit- und konzentrationsabhngigen Herunterregulation von BH4, BH2 und Biopterin, wobei ebenso das BH4 / BH2 -Verhltnis vermindert wurde. Beide Enzyme, GCH1 genauso wie DHFR, wurden auf mRNA- und Proteinebene herunterreguliert, was auf einen Effekt von GCs auf beide rnBH4-produzierenden Signalwege schlieen lsst. Nach Behandlung mit DEX wurde die Produktion von NO in Endothelzellen mageblich vermindert. In ROS-Messungen zeigte sich eine Tendenz hin zu einer eNOS-Entkopplung, jedoch war es mit unserem experimentellen Aufbau nicht mglich, diese endgltig zu beweisen.rnZusammenfassend lsst sich sagen, dass die Behandlung mit GCs zu Vernderungen in beiden untersuchten Systemen, den NADPH Oxidasen ebenso wie dem eNOS-NO System, fhrte. DEX erhhte die Expression von Nox1 in glatten Muskelzellen und reduzierte die Nox4-Expression in Endothelzellen. Gleichzeitig verminderte DEX die Verfgbarkeit von BH4 und inhibierte die Phosphorylierung / Aktivitt von eNOS. Mithilfe weiterer Studien muss die endgltige Beteiligung von NADPH Oxidasen und einer eNOS-Entkopplung an oxidativem Stress in GC-HT abschlieend aufgeklrt werden.rn
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Aseptic loosening of metal implants is mainly attributed to the formation of metal degradation products. These include particulate debris and corrosion products, such as metal ions (anodic half-reaction) and ROS (cathodic half-reaction). While numerous clinical studies describe various adverse effects of metal degradation products, detailed knowledge of metal-induced cellular reactions, which might be important for possible therapeutic intervention, is not comprehensive. Since endothelial cells are involved in inflammation and angiogenesis, two processes which are critical for wound healing and integration of metal implants, the effects of different metal alloys and their degradation products on these cells were investigated. Endothelial cells on Ti6Al4V alloy showed signs of oxidative stress, which was similar to the response of endothelial cells to cathodic partial reaction of corrosion induced directly on Ti6Al4V surfaces. Furthermore, oxidative stress on Ti6Al4V alloy reduced the pro-inflammatory stimulation of endothelial cells by TNF- and LPS. Oxidative stress and other stress-related responses were observed in endothelial cells in contact with Co28Cr6Mo alloy. Importantly, these features could be reduced by coating Co28Cr6Mo with a TiO2 layer, thus favouring the use of such surface modification in the development of medical devices for orthopaedic surgery. The reaction of endothelial cells to Co28Cr6Mo alloy was partially similar to the effects exerted by Co2+, which is known to be released from metal implants. Co2+ also induced ROS formation and DNA damage in endothelial cells. This correlated with p53 and p21 up-regulation, indicating the possibility of cell cycle arrest. Since CoCl2 is used as an hypoxia-mimicking agent, HIF-1-dependence of cellular responses to Co2+ was studied in comparison to anoxia-induced effects. Although important HIF-1-dependent genes were identified, a more detailed analysis of microarray data will be required to provide additional information about the mechanisms of Co2+ action. All these reactions of endothelial cells to metal degradation products might play their role in the complex processes taking place in the body following metal device implantation. In the worst case this can lead to aseptic loosening of the implant and requirement for revision surgery. Knowledge of molecular mechanisms of metal-induced responses will hopefully provide the possibility to interfere with undesirable processes at the implant/tissue interface, thus extending the life-time of the implant and the overall success of metal implant applications.
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Studies on conjugated linoleic acid ingestion and its effect on cardiac tissue are necessary for the safe utilization of this compound as supplement for weight loss. Male Wistar 24-rats were divided into four groups (n = 6):(C)given standard chow, water and 0.5 ml saline, twice a week by gavage; (C-CLA)receiving standard chow, water and 0.5 ml of conjugated linoleic acid, twice a week, by gavage; (S)given standard chow, saline by gavage, and 30% sucrose in its drinking water; (S-CLA)receiving standard chow, 30% sucrose in its drinking water and conjugated linoleic acid. After 42 days of treatment S rats had obesity with increased abdominal-circumference, dyslipidemia, oxidative stress and myocardial lower citrate synthase(CS) and higher lactate dehydrogenase(LDH) activities than C. Conjugated linoleic acid had no effects on morphometric parameters in C-CLA, as compared to C, but normalized morphometric parameters comparing S-CLA with S. There was a negative correlation between abdominal adiposity and resting metabolic rate. Conjugated linoleic acid effect, enhancing fasting-VO2/surface area, postprandial-carbohydrate oxidation and serum lipid hydroperoxide resembled to that of the S group. Conjugated linoleic acid induced cardiac oxidative stress in both fed conditions, and triacylglycerol accumulation in S-CLA rats. Conjugated linoleic acid depressed myocardial LDH comparing C-CLA with C, and beta-hydroxyacyl-coenzyme-A dehydrogenase/CS ratio, comparing S-CLA with S. In conclusion, dietary conjugated linoleic acid supplementation for weight loss can have long-term effects on cardiac health. Conjugated linoleic acid, isomers c9, t11 and t10, c12 presented undesirable pro-oxidant effect and induced metabolic changes in cardiac tissue. Nevertheless, despite its effect on abdominal adiposity in sucrose-rich diet condition, conjugated linoleic acid may be disadvantageous because it can lead to oxidative stress and dyslipidemic profile. (c) 2007 Elsevier B.V All rights reserved.
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Objective We investigated the effects of high-fat diet-induced obesity on vascular proinflammatory factors and oxidative stress on endothelium-dependent relaxation of the aorta. Methods Female Swiss mice were submitted to a high-fat diet for 16 weeks. At the end of the experimental period, we evaluated blood pressure, relaxation in response to acetylcholine in aortic rings in the absence and the presence of the superoxide anion scavenger, superoxide dismutase (SOD, 150 U/ml), and the nuclear factor (NF)-kappa B inhibitor, sodium salicylate (5 mmol/l). Aortic protein expression of endothelial nitric oxide synthase, Cu/Zn-SOD, NF-kappa B, I kappa B-alpha, and proinflammatory cytokines were also evaluated. Results Obese mice presented higher systolic and diastolic blood pressure than control mice (P<0.05). The relaxation of aortas to acetylcholine, but not to sodium nitroprusside, was significantly decreased in obese mice and was corrected by both SOD and sodium salicylate (P<0.05). The protein expression of endothelial nitric oxide synthase and Cu/Zn-SOD was significantly decreased in aorta from obese mice (P<0.05). Total p65 NF-kappa B subunit protein expression was not affected by obesity, but the protein expression of NF-kappa B inhibitor I kappa B-alpha was lower in aorta from obese mice (P<0.05). There were no significant differences in the interleukin (IL)-1 beta and IL-6 protein expression between groups. In contrast, the expression of TNF-alpha was significantly increased in aortas from obese mice. Conclusion Our resultssuggest that the reducedantioxidant defense and the local NF-kappa B pathway play an important role in the impairment of endothelium-dependent relaxation in aorta from obese mice. J Hypertens 28: 2111-2119 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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<p>Ischaemic strokes evoke blood-brain barrier (BBB) disruption and oedema formation through a series of mechanisms involving Rho-kinase activation. Using an animal model of human focal cerebral ischaemia, this study assessed and confirmed the therapeutic potential of Rho-kinase inhibition during the acute phase of stroke by displaying significantly improved functional outcome and reduced cerebral lesion and oedema volumes in fasudil- versus vehicle-treated animals. Analyses of ipsilateral and contralateral brain samples obtained from mice treated with vehicle or fasudil at the onset of reperfusion plus 4 h post-ischaemia or 4 h post-ischaemia alone revealed these benefits to be independent of changes in the activity and expressions of oxidative stress- and tight junction-related parameters. However, closer scrutiny of the same parameters in brain microvascular endothelial cells subjected to oxygen-glucose deprivation reperfusion revealed marked increases in prooxidant NADPH oxidase enzyme activity, superoxide anion release and in expressions of antioxidant enzyme catalase and tight junction protein claudin-5. Cotreatment of cells with Y-27632 prevented all of these changes and protected in vitro barrier integrity and function. These findings suggest that inhibition of Rho-kinase after acute ischaemic attacks improves cerebral integrity and function through regulation of endothelial cell oxidative stress and reorganization of intercellular junctions. Inhibition of Rho-kinase (ROCK) activity in a mouse model of human ischaemic stroke significantly improved functional outcome while reducing cerebral lesion and oedema volumes compared to vehicle-treated counterparts. Studies conducted with brain microvascular endothelial cells exposed to OGD R in the presence of Y-27632 revealed restoration of intercellular junctions and suppression of prooxidant NADPH oxidase activity as important factors in ROCK inhibition-mediated BBB protection.</p>
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Le vieillissement vasculaire est caractris par une dysfonction de lendothlium. De nombreux facteurs de risque cardiovasculaire tels que lobsit et lhypertension prdisposent lendothlium un stress oxydant lev aboutissant une dysfonction endothliale, celle-ci tant communment accompagne dune diminution de la biodisponibilit du monoxyde dazote. Bien que la fonction endothliale soit un dterminant majeur de la prdiction du risque cardiovasculaire des patients, son valuation individuelle reste trs limite. En consquence, il existe un intrt scientifique grandissant pour la recherche de meilleurs biomarqueurs. LAngiopoitine like-2 (angptl2), une protine identifie rcemment, joue un rle pro-inflammatoire et pro-oxydant dans plusieurs dsordres causs par une inflammation chronique allant de lobsit lathrosclrose. Linflammation et un stress oxydant accru ont t tablis comme des mcanismes sous-jacents lapparition dune dysfonction endothliale, cest pourquoi ce travail met laccent sur le rle de langptl2 dans la dysfonction endothliale. Plus prcisment, ce travail vise : 1) dterminer les effets aigus de langptl2 sur la fonction endothliale, 2) caractriser la fonction endothliale et la contribution des diffrents facteurs relaxants drivs de l'endothlium (EDRF) dans plusieurs lits vasculaires, et ce, dans un modle de souris rprimant lexpression de langptl2 (knock-down, KD), et 3) examiner si l'absence d'expression angptl2 protge contre la dysfonction endothliale induite par un rgime riche en graisses (HFD) ou par perfusion d'angiotensine II (angII) chez la souris. Dans la premire tude, lincubation aigue avec de langptl2 recombinante induit une dysfonction endothliale dans les artres fmorales isoles de souris de type sauvage (WT), probablement en raison dune production accrue d'espces ractives oxygnes. Les artres fmorales de souris angptl2 KD prsentent une meilleure fonction endothliale en comparaison aux souris WT, vraisemblablement par une plus grande contribution de la prostacycline dans la vasodilatation. Aprs 3 mois dune dite HFD, les principaux EDRF respectifs des artres fmorales et msentriques sont conservs uniquement dans les souris angptl2 KD. Cette prservation est associe un meilleur profil mtabolique, une moindre accumulation de triglycrides dans le foie et des adipocytes de plus petite taille. De plus, lexpression de gnes inflammatoires dans ces tissus adipeux nest augmente que chez les souris WT. Dans la seconde tude, labsence dangptl2 rsulte en une production accrue de monoxyde dazote dans les artres crbrales isoles par rapport celles des souris WT. La perfusion chronique dangII provoque, seulement chez les souris WT, une dysfonction endothliale crbrale probablement par le biais dune augmentation de la production despces ractives oxygnes, probablement driv des NADPH oxydase 1 et 2, ainsi que l'augmentation des facteurs constricteurs drivs de lendothlium issus de la cyclo-oxygnase. En revanche, lapocynine rduit la dilatation crbrale chez les souris KD traites langII, ce qui suggre le recrutement potentiel dune voie de signalisation compensatoire impliquant les NADPH oxydases et qui aurait un effet vaso-dilatateur. Ces tudes suggrent fortement que langptl2 peut avoir un impact direct sur la fonction endothliale par ses proprits pro-inflammatoire et pro-oxydante. Dans une optique dapplication la pratique clinique, les niveaux sanguins dangptl2 pourraient tre un bon indicateur de la fonction endothliale.
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Cardiovascular disease is less frequent in premenopausal women than in age-matched men or postmenopausal women. Moreover, the marked age-related decline in serum dehydroepiandrosterone (DHEA) level has been associated to cardiovascular disease. The aim of this study was to evaluate the effects of DHEA treatment on vascular function in ovariectomized rats. At 8 weeks of age, female Wistar rats were ovariectomized (OVX) or sham (SHAM) operated and 8 weeks after surgery both groups were treated with vehicle or DHEA (10 mg kg-1 week-1) for 3 weeks. Aortic rings were used to evaluate the vasoconstrictor response to phenylephrine (PHE) and the relaxation responses to acetylcholine (ACh) and sodium nitroprusside (SNP). Tissue reactive oxygen species (ROS) production and SOD, NADPH oxidase and eNOS protein expression were analysed. PHE-induced contraction was increased in aortic rings from OVX compared to SHAM, associated with a reduction in NO bioavailability. Furthermore, the relaxation induced by ACh was reduced in arteries from OVX, while SNP relaxation did not change. The incubation of aortic rings with SOD or apocynin restored the enhanced PHE-contraction and the impaired ACh-relaxation only in OVX. DHEA treatment corrected the increased PHE contraction and the impaired ACh-induced relaxation observed in OVX by an increment in NO bioavailability and decrease in ROS production. Besides, DHEA treatment restores the reduced Cu/Zn-SOD protein expression and eNOS phosphorylation and the increased NADPH oxidase protein expression in the aorta of OVX rats. The present results suggest an important action of DHEA, improving endothelial function in OVX rats by acting as an antioxidant and enhancing the NO bioavailability.
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Fundao de Amparo Pesquisa do Estado de So Paulo (FAPESP)
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Background/Aims: beta(2)-adrenoceptor (beta(2)-AR) activation induces smooth muscle relaxation and endothelium-derived nitric oxide (NO) release. However, whether endogenous basal beta(2)-AR activity controls vascular redox status and NO bioavailability is unclear. Thus, we aimed to evaluate vascular reactivity in mice lacking functional beta(2)-AR (beta 2KO), focusing on the role of NO and superoxide anion. Methods and Results: Isolated thoracic aortas from beta 2KO and wild-type mice (WT) were studied. beta 2KO aortas exhibited an enhanced contractile response to phenylephrine compared to WT. Endothelial removal and L-NAME incubation increased phenylephrine-induced contraction, abolishing the differences between beta 2KO and WT mice. Basal NO availability was reduced in aortas from beta 2KO mice. Incubation of beta 2KO aortas with superoxide dismutase or NADPH inhibitor apocynin restored the enhanced contractile response to phenylephrine to WT levels. beta 2KO aortas exhibited oxidative stress detected by enhanced dihydroethidium fluorescence, which was normalized by apocynin. Protein expression of eNOS was reduced, while p47(phox) expression was enhanced in beta 2KO aortas. Conclusions: The present results demonstrate for the first time that enhanced NADPH-derived superoxide anion production is associated with reduced NO bioavailability in aortas of beta 2KO mice. This study extends the knowledge of the relevance of the endogenous activity of beta(2)-AR to the maintenance of the vascular physiology. Copyright (C) 2012 S. Karger AG, Basel
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Chronic kidney disease (CKD) is associated with increased cardiovascular risk in comparison with the general population. This can be observed even in the early stages of CKD, and rises in proportion to the degree of renal impairment. Not only is cardiovascular disease (CVD) more prevalent in CKD, but its nature differs too, with an excess of morbidity and mortality associated with congestive cardiac failure, arrhythmia and sudden death, as well as the accelerated atherosclerosis which is also observed. Conventional cardiovascular risk factors such as hypertension, dyslipidaemia, obesity, glycaemia and smoking, are highly prevalent amongst patients with CKD, although in many of these examples the interaction between risk factor and disease differs from that which exists in normal renal function. Nevertheless, the extent of CVD cannot be fully explained by these conventional risk factors, and non-conventional factors specific to CKD are now recognised to contribute to the burden of CVD. Oxidative stress is a state characterised by excessive production of reactive oxygen species (ROS) and other radical species, a reduction in the capacity of antioxidant systems, and disturbance in normal redox homeostasis with depletion of protective vascular signalling molecules such as nitric oxide (NO). This results in oxidative damage to macromolecules such as lipids, proteins and DNA which can alter their functionality. Moreover, many enzymes are sensitive to redox regulation such that oxidative modification to cysteine thiol groups results in activation of signalling cascades which result in adverse cardiovascular effects such as vascular and endothelial dysfunction. Endothelial dysfunction and oxidative stress are present in association with many conventional cardiovascular risk factors, and can be observed even prior to the development of overt, clinical, vascular pathology, suggesting that these phenomena represent the earliest stages of CVD. In the presence of CKD, there is increased ROS production due to upregulated NADPH oxidase (NOX), increase in a circulating asymmetric dimethylarginine (ADMA), uncoupling of endothelial nitric oxide synthase (eNOS) as well as other mechanisms. There is also depletion in exogenous antioxidants such as ascorbic acid and tocopherol, and a reduction in activity of endogenous antioxidant systems regulated by the master gene regulator Nrf-2. In previous studies, circulating markers of oxidative stress have been shown to be increased in CKD, together with a reduction in endothelial function in a stepwise fashion relating to the severity of renal impairment. Not only is CVD linked to oxidative stress, but the progression of CKD itself is also in part dependent on redox sensitive mechanisms. For example, administration of the ROS scavenger tempol attenuates renal injury and reduces renal fibrosis seen on biopsy in a mouse model of CKD, whilst conversely, supplementation with the NOS inhibitor L-NAME causes proteinuria and renal impairment. Previous human studies examining the effect of antioxidant administration on vascular and renal function have been conflicting however. The work contained in this thesis therefore examines the effect of antioxidant administration on vascular and endothelial function in CKD. Firstly, 30 patients with CKD stages 3 5, and 20 matched hypertensive controls were recruited. Participants with CKD had lower ascorbic acid, higher TAP and ADMA, together with higher augmentation index and pulse wave velocity. There was no difference in baseline flow mediated dilatation (FMD) between groups. Intravenous ascorbic acid increased TAP and O2-, and reduced central BP and augmentation index in both groups, and lowered ADMA in the CKD group only. No effect on FMD was observed. The effects of ascorbic acid on kidney function was then investigated, however this was hindered by the inherent drawbacks of existing methods of non-invasively measuring kidney function. Arterial spin labelling MRI is an emerging imaging technique which allows measurement of renal perfusion without administration of an exogenous contrast agent. The technique relies upon application of an inversion pulse to blood within the vasculature proximal to the kidneys, which magnetically labels protons allowing measurement upon transit to the kidney. At the outset of this project local experience using ASL MRI was limited and there ensued a prolonged pre-clinical phase of testing with the aim of optimising imaging strategy. A study was then designed to investigate the repeatability of ASL MRI in a group of 12 healthy volunteers with normal renal function. The measured T1 longitudinal relaxation times and ASL MRI perfusion values were in keeping with those found in the literature; T1 time was 1376 ms in the cortex and 1491 ms in the whole kidney ROI, whilst perfusion was 321 mL/min/100g in the cortex, and 228 mL/min/100g in the whole kidney ROI. There was good reproducibility demonstrated on Bland Altman analysis, with a CVws was 9.2% for cortical perfusion and 7.1% for whole kidney perfusion. Subsequently, in a study of 17 patients with CKD and 24 healthy volunteers, the effects of ascorbic acid on renal perfusion was investigated. Although no change in renal perfusion was found following ascorbic acid, it was found that ASL MRI demonstrated significant differences between those with normal renal function and participants with CKD stages 3 5, with increased cortical and whole kidney T1, and reduced cortical and whole kidney perfusion. Interestingly, absolute perfusion showed a weak but significant correlation with progression of kidney disease over the preceding year. Ascorbic acid was therefore shown to have a significant effect on vascular biology both in CKD and in those with normal renal function, and to reduce ADMA only in patients with CKD. ASL MRI has shown promise as a non-invasive investigation of renal function and as a biomarker to identify individuals at high risk of progressive renal impairment.
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Chronic intermittent hypoxia (CIH) causes upper airway muscle dysfunction. We hypothesized that the superoxide generating NADPH oxidase (NOX) is upregulated in CIH-exposed muscle causing oxidative stress. Adult male Wistar rats were exposed to intermittent hypoxia (5% O2 at the nadir for 90 s followed by 210 s of normoxia), for 8 h per day for 14 days. The effect of CIH exposure on the expression of NOX subunits, total myosin and 4-hydroxynonenal (4-HNE) protein adducts in sternohyoid muscle was determined by western blotting and densitometry. Sternohyoid protein free thiol and carbonyl group contents were determined by 1D electrophoresis using specific fluorophore probes. Aconitase and glutathione reductase activities were measured as indices of oxidative stress. HIF-1 content and key oxidative and glycolytic enzyme activities were determined. Contractile properties of sternohyoid muscle were determined ex vivo in the absence and presence of apocynin (putative NOX inhibitor). We observed an increase in NOX 2 and p47 phox expression in CIH-exposed sternohyoid muscle with decreased aconitase and glutathione reductase activities. There was no evidence, however, of increased lipid peroxidation or protein oxidation in CIH-exposed muscle. CIH exposure did not affect sternohyoid HIF-1 content or aldolase, lactate dehydrogenase, or glyceraldehyde-3-phosphate dehydrogenase activities. Citrate synthase activity was also unaffected by CIH exposure. Apocynin significantly increased sternohyoid force and power. We conclude that CIH exposure upregulates NOX expression in rat sternohyoid muscle with concomitant modest oxidative stress but it does not result in a HIF-1-dependent increase in glycolytic enzyme activity. Constitutive NOX activity decreases sternohyoid force and power. Our results implicate NOX-dependent reactive oxygen species in CIH-induced upper airway muscle dysfunction which likely relates to redox modulation of key regulatory proteins in excitation-contraction coupling.
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<p>The extent of absorption of dietary advanced glycation end products (AGEs) is not fully known. The possible physiological impact of these absorbed components on inflammatory processes has been studied little and was the aim of this investigation. Aqueous solutions of bovine casein and glucose were heated at 95 degrees C for 5 h to give AGE-casein (AGE-Cas). Simulated stomach and small intestine digestion of AGE-Cas and dialysis (molecular mass cutoff of membrane = 1 kDa) resulted in a low molecular mass (LMM) fraction of digestion products, which was used to prepare bovine serum albumin (BSA)-LMM-AGE-Cas complexes. Stimulation of human microvascular endothelial cells with BSA-LMM-AGE-Cas complexes significantly increased mRNA expression of the receptor of AGE (RAGE), galectin-3 (AGE-113), tumor necrosis factor alpha, and a marker of the mitogen-activated protein kinase pathway (MAPK-1), as well as p65NF-kappa B activation. Cells treated with LMM digestion products of AGE-Cas significantly increased AGE-R3 mRNA expression. Intracellular reactive oxygen species production increased significantly in cells challenged with BSA-LMM-AGE-Cas and LMM-AGE-Cas. In conclusion, in an in vitro cell system, digested dietary AGEs complexed with serum albumin play a role in the regulation of RAGE and down-stream inflammatory pathways. AGE-R3 may protect against these effects.</p>
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Background and aims<br/><br/>Public health campaigns recommend increased fruit and vegetable (FV) consumption as an effective means of cardiovascular risk reduction. During an 8 week randomised control trial among hypertensive volunteers, we noted significant improvements in endothelium-dependent vasodilatation with increasing FV consumption. Circulating indices of inflammation, endothelial activation and insulin resistance are often employed as alternative surrogates for systemic arterial health. The responses of several such biomarkers to our previously described FV intervention are reported here.<br/>Methods and results<br/><br/>Hypertensive volunteers were recruited from medical outpatient clinics. After a common 4 week run-in period during which FV consumption was limited to 1 portion per day, participants were randomised to 1, 3 or 6 portions daily for 8 weeks. Venous blood samples for biomarker analyses were collected during the pre and post-intervention vascular assessments. A total of 117 volunteers completed the 12 week study. Intervention-related changes in circulating levels of high sensitivity C-reactive protein (hsCRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) did not differ significantly between FV groups. Similarly, there were no significant between group differences of change in homeostasis model assessment (HOMA) scores.<br/>Conclusions<br/><br/>Despite mediating a significant improvement in acetylcholine induced vasodilatation, increased FV consumption did not affect a calculated measure of insulin resistance or concentrations of the circulating biomarkers measured during this study. Functional indices of arterial health such as endothelium-dependent vasomotion are likely to provide more informative cardiovascular end-points during short-term dietary intervention trials.
