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  • 1
    Online Resource
    Online Resource
    High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo
    Portland Press Ltd. ; 2009
    In:  Biochemical Journal Vol. 417, No. 1 ( 2009-01-01), p. 183-193
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 417, No. 1 ( 2009-01-01), p. 183-193
    Abstract: NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is an important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role in NAFLD initiation and progression to the more serious condition of NASH (non-alcoholic steatohepatitis). Herein we hypothesize that mitochondrial defects induced by exposure to a HFD (high fat diet) contribute to a hypoxic state in liver and this is associated with increased protein modification by RNS (reactive nitrogen species). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories (1 cal≈4.184 J) from fat respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, NO (nitric oxide)-dependent control of respiration, and 3-NT (3-nitrotyrosine), a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triacylglycerols, increased CYP2E1 (cytochrome P450 2E1) and iNOS (inducible nitric oxide synthase) protein, and significantly enhanced hypoxia in the pericentral region of the liver. Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls. In addition, accumulation of 3-NT paralleled the hypoxia gradient in vivo and 3-NT levels were increased in mitochondrial proteins. Liver mitochondria from mice fed the HFD for 16 weeks exhibited depressed state 3 respiration, uncoupled respiration, cytochrome c oxidase activity, and mitochondrial membrane potential. These findings indicate that chronic exposure to a HFD negatively affects the bioenergetics of liver mitochondria and this probably contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20080868
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2009
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Oxidized LDL induces mitochondrially associated reactive oxygen/nitrogen species formation in endothelial cells
    American Physiological Society ; 2005
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 289, No. 2 ( 2005-08), p. H852-H861
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 289, No. 2 ( 2005-08), p. H852-H861
    Abstract: Exposure of cells to complex mixtures of oxidized lipids such as those found in oxidized low-density lipoprotein (oxLDL) induce reactive oxygen and nitrogen species (ROS/RNS) formation. The source of the ROS/RNS within cells is unknown; it is thought they may be involved in redox cell signaling. Although this possibility was initially overlooked, it is becoming clear that mitochondria, which are a source of superoxide and hydrogen peroxide, may play a critical role in the response of cells on exposure to oxidized lipids. In this study, we tested the possibility that mitochondria are a potential source of oxLDL-dependent formation of ROS/RNS in endothelial cells. Using confocal microscopy, we demonstrated that a significant proportion of oxLDL-dependent dichlorodihydrofluorescein (DCF) fluorescence is colocalized to mitochondria. In support of this concept, rho0 endothelial cells showed a substantial decrease in ROS/RNS formation stimulated by oxLDL. In contrast, mostly nonmitochondrial DCF fluorescence was detected in cells exposed to an extracellular source of hydrogen peroxide. The exposure of cells to a nitric oxide synthase inhibitor and urate resulted in a decrease in oxLDL-induced DCF fluorescence that was restored by addition of nitric oxide donors to the medium. Taken together, these results suggest that oxLDL-dependent DCF fluorescence is mitochondrially associated and may be due to the formation of peroxynitrite.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00015.2005
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2005
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Hydrogen sulfide mediates vasoactivity in an O 2 -dependent manner
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 292, No. 4 ( 2007-04), p. H1953-H1960
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 292, No. 4 ( 2007-04), p. H1953-H1960
    Abstract: Hydrogen sulfide (H 2 S) has recently been shown to have a signaling role in vascular cells. Similar to nitric oxide (NO), H 2 S is enzymatically produced by amino acid metabolism and can cause posttranslational modification of proteins, particularly at thiol residues. Molecular targets for H 2 S include ATP-sensitive K + channels, and H 2 S may interact with NO and heme proteins such as cyclooxygenase. It is well known that the reactions of NO in the vasculature are O 2 dependent, but this has not been addressed in most studies designed to elucidate the role of H 2 S in vascular function. This is important, since H 2 S reactions can be dramatically altered by the high concentrations of O 2 used in cell culture and organ bath experiments. To test the hypothesis that the effects of H 2 S on the vasculature are O 2 dependent, we have measured real-time levels of H 2 S and O 2 in respirometry and vessel tension experiments, as well as the associated vascular responses. A novel polarographic H 2 S sensor developed in our laboratory was used to measure H 2 S levels. Here we report that, in rat aorta, H 2 S concentrations that mediate rapid contraction at high O 2 levels cause rapid relaxation at lower physiological O 2 levels. At high O 2 , the vasoconstrictive effect of H 2 S suggests that it may not be H 2 S per se but, rather, a putative vasoactive oxidation product that mediates constriction. These data are interpreted in terms of the potential for H 2 S to modulate vascular tone in vivo.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.01193.2006
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Induction of the permeability transition and cytochrome c release by 15-deoxy-Δ12,14-prostaglandin J2 in mitochondria
    Portland Press Ltd. ; 2006
    In:  Biochemical Journal Vol. 394, No. 1 ( 2006-02-15), p. 185-195
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 394, No. 1 ( 2006-02-15), p. 185-195
    Abstract: The electrophilic lipid 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is known to allow adaptation to oxidative stress in cells at low concentrations and apoptosis at high levels. The mechanisms leading to adaptation involve the covalent modification of regul-atory proteins, such as Keap1, and augmentation of antioxidant defences in the cell. The targets leading to apoptosis are less well defined, but mitochondria have been indirectly implicated in the mechanisms of cell death mediated by electrophilic lipids. To determine the potential of electrophilic cyclopentenones to induce pro-apoptotic effects in the mitochondrion, we used isolated liver mitochondria and demonstrated that 15d-PGJ2 promotes Ca2+-induced mitochondrial swelling and cytochrome c release. The mechanisms involved are consistent with direct modification of protein thiols in the mitochondrion, rather than secondary formation of reactive oxygen species or lipid peroxidation. Using proteomic analysis in combination with biotinylated 15d-PGJ2, we were able to identify 17 potential targets of the electrophile-responsive proteome in isolated liver mitochondria. Taken together, these results suggest that electrophilic lipid oxidation products can target a sub-proteome in mitochondria, and this in turn results in the transduction of the electrophilic stimulus to the cell through cytochrome c release.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20051259
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2006
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    S-Nitrosation and thiol switching in the mitochondrion: a new paradigm for cardioprotection in ischaemic preconditioning
    Portland Press Ltd. ; 2008
    In:  Biochemical Journal Vol. 412, No. 2 ( 2008-06-01), p. e11-e13
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 412, No. 2 ( 2008-06-01), p. e11-e13
    Abstract: Understanding the molecular mechanisms through which the heart could be protected from ischaemic injury is of major interest and offers a potential route for the development of new therapies. Recently, several studies have uncovered intriguing relationships between nitric oxide-induced protein thiol modifications and the cardioprotected phenotype. In a highly cited, seminal article published in the Biochemical Journal in 2006, Burwell and colleagues addressed this issue and provided direct evidence for S-nitrosation of complex I of the mitochondrial electron transport chain. These authors were the first to show increased S-nitrosation of mitochondrial proteins from hearts subjected to the cardioprotective process known as ischaemic preconditioning. This study has paved the way for further investigations that collectively reveal a potential link between the mitochondrial S-nitrosoproteome and ischaemic preconditioning.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20080716
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2008
    detail.hit.zdb_id: 1473095-9
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  • 6
    Online Resource
    Online Resource
    Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal
    Portland Press Ltd. ; 2009
    In:  Biochemical Journal Vol. 424, No. 1 ( 2009-11-15), p. 99-107
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 424, No. 1 ( 2009-11-15), p. 99-107
    Abstract: Mitochondria play a critical role in mediating the cellular response to oxidants formed during acute and chronic cardiac dysfunction. It is widely assumed that, as cells are subjected to stress, mitochondria are capable of drawing upon a ‘reserve capacity’ which is available to serve the increased energy demands for maintenance of organ function, cellular repair or detoxification of reactive species. This hypothesis further implies that impairment or depletion of this putative reserve capacity ultimately leads to excessive protein damage and cell death. However, it has been difficult to fully evaluate this hypothesis since much of our information about the response of the mitochondrion to oxidative stress derives from studies on mitochondria isolated from their cellular context. Therefore the goal of the present study was to determine whether ‘bioenergetic reserve capacity’ does indeed exist in the intact myocyte and whether it is utilized in response to stress induced by the pathologically relevant reactive lipid species HNE (4-hydroxynonenal). We found that intact rat neonatal ventricular myocytes exhibit a substantial bioenergetic reserve capacity under basal conditions; however, on exposure to pathologically relevant concentrations of HNE, oxygen consumption was increased until this reserve capacity was depleted. Exhaustion of the reserve capacity by HNE treatment resulted in inhibition of respiration concomitant with protein modification and cell death. These data suggest that oxidized lipids could contribute to myocyte injury by decreasing the bioenergetic reserve capacity. Furthermore, these studies demonstrate the utility of measuring the bioenergetic reserve capacity for assessing or predicting the response of cells to stress.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20090934
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2009
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Evidence for oxygen as the master regulator of the responsiveness of soluble guanylate cyclase and cytochrome c oxidase to nitric oxide
    Portland Press Ltd. ; 2007
    In:  Biochemical Journal Vol. 405, No. 2 ( 2007-07-15)
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 405, No. 2 ( 2007-07-15)
    Abstract: Haem is used as a versatile receptor for redox active molecules; most notably NO (nitric oxide) and oxygen. Three haem-containing proteins, myoglobin, haemoglobin and cytochrome c oxidase, are now known to bind NO, and in all these cases competition with oxygen plays an important role in the biological outcome. NO also binds to the haem group of sGC (soluble guanylate cyclase) and initiates signal transduction through the formation of cGMP in a process that is oxygen-independent. From biochemical studies, it has been shown that sGC is substantially more sensitive to NO than is cytochrome c oxidase, but a direct comparison in a cellular setting under various oxygen levels has not been reported previously. In this issue of the Biochemical Journal, Cadenas and co-workers reveal how oxygen can act as the master regulator of the relative sensitivity of the cytochrome c oxidase and sGC signalling pathways to NO. These findings have important implications for our understanding of the interplay between NO and oxygen in both physiology and the pathology of diseases associated with hypoxia.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20070590
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2007
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Hydrogen sulfide mediates the vasoactivity of garlic
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 46 ( 2007-11-13), p. 17977-17982
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 46 ( 2007-11-13), p. 17977-17982
    Abstract: The consumption of garlic is inversely correlated with the progression of cardiovascular disease, although the responsible mechanisms remain unclear. Here we show that human RBCs convert garlic-derived organic polysulfides into hydrogen sulfide (H 2 S), an endogenous cardioprotective vascular cell signaling molecule. This H 2 S production, measured in real time by a novel polarographic H 2 S sensor, is supported by glucose-maintained cytosolic glutathione levels and is to a large extent reliant on reduced thiols in or on the RBC membrane. H 2 S production from organic polysulfides is facilitated by allyl substituents and by increasing numbers of tethering sulfur atoms. Allyl-substituted polysulfides undergo nucleophilic substitution at the α carbon of the allyl substituent, thereby forming a hydropolysulfide (RS n H), a key intermediate during the formation of H 2 S. Organic polysulfides (R-S n -R′; n 〉 2) also undergo nucleophilic substitution at a sulfur atom, yielding RS n H and H 2 S. Intact aorta rings, under physiologically relevant oxygen levels, also metabolize garlic-derived organic polysulfides to liberate H 2 S. The vasoactivity of garlic compounds is synchronous with H 2 S production, and their potency to mediate relaxation increases with H 2 S yield, strongly supporting our hypothesis that H 2 S mediates the vasoactivity of garlic. Our results also suggest that the capacity to produce H 2 S can be used to standardize garlic dietary supplements.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0705710104
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Interaction of electrophilic lipid oxidation products with mitochondria in endothelial cells and formation of reactive oxygen species
    American Physiological Society ; 2006
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 290, No. 5 ( 2006-05), p. H1777-H1787
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 290, No. 5 ( 2006-05), p. H1777-H1787
    Abstract: Electrophilic lipids, such as 4-hydroxynonenal (HNE), and the cyclopentenones 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) and 15-J 2 -isoprostane induce both reactive oxygen species (ROS) formation and cellular antioxidant defenses, such as heme oxygenase-1 (HO-1) and glutathione (GSH). When we compared the ability of these distinct electrophiles to stimulate GSH and HO-1 production, the cyclopentenone electrophiles were somewhat more potent than HNE. Over the concentration range required to observe equivalent induction of GSH, dichlorofluorescein fluorescence was used to determine both the location and amounts of electrophilic lipid-dependent ROS formation in endothelial cells. The origin of the ROS on exposure to these compounds was largely mitochondrial. To investigate the possibility that the increased ROS formation was due to mitochondrial localization of the lipids, we prepared a novel fluorescently labeled form of the electrophilic lipid 15d-PGJ 2 . The lipid demonstrated strong colocalization with the mitochondria, an effect which was not observed by using a fluorescently labeled nonelectrophilic lipid. The role of mitochondria was confirmed by using cells deficient in functional mitochondria. On the basis of these data, we propose that ROS formation in endothelial cells is due to the direct interaction of these lipids with the organelle.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.01087.2005
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2006
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    The Wellcome world of reactive nitrogen species
    Portland Press Ltd. ; 2009
    In:  Biochemical Journal
    Details
    In: Biochemical Journal, Portland Press Ltd.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20081959
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2009
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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