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Supplementation with omega-3 fatty acids potentiates glutathione oxidation in human airway epithelial cells exposed to ozone
A. Newman / Free Radical Biology and Medicine 128 (2018) S21–S46
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Resveratrol improves endothelial function in diabetic and obese mice through SIRT1-PPARδ Wai San Cheangn University of Macau, China
SIRT1 activation reduces vascular oxidative stress, inhibits inflammatory responses, and retards cellular senescence in mouse models of diabetes. However, whether SIRT1 also plays a protective role in vascular dysfunction of diabetic and obese mice is not fully characterized. Previous work showed that PPARδ is beneficial in diabetic vascular dysfunction. Whether PPARδ is involved in the effect of SIRT1 on vascular endothelial function is unknown. We used mice with overexpression of endothelial cell-specific human SIRT1 (SIRT1-Tg) and dominant negative SIRT1 (SIRT1-mut) fed with normal chow and high fat diet to show expression of functional SIRT1 in endothelium protects against vascular dysfunction in diet-induced obese mice. Endothelial overexpression of SIRT1 improved endothelium-dependent dilation in aorta treated with risk factors including high glucose, angiotensin II, and lysophosphatidylcholine. Wild type (Ppard-wt) and PPARδ knockout (Ppard-mut) mice on high fat diet were treated with resveratrol. Resveratrol treatment improves endothelial function in Ppard-wt but not Ppard-mut mice. Experiments on isolated arteries ex vivo also showed that the effect of SIRT1 activator resveratrol or CAY10602 can be inhibited by PPARδ antagonist GSK0660. Resveratrol increased PPARδ transcriptional activity in endothelial cells. Results demonstrated here indicated that PPARδ contributes to the beneficial effect of SIRT1 against endothelial dysfunction in diabetic and obese mice. These results help to understand SIRT1-based strategy for treating vascular and metabolic dysfunction in the context of obesity and insulin resistance.
https://doi.org/10.1016/j.freeradbiomed.2018.10.008
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Glypican-1 mediates endothelial hyperpermeability in a model of acute heart failure Andreia Chignalia 1, n, Ayman Isbatan 1, Barry Borlaug 2, Guochang Hu 1, Randal Dull 3 1
University of Illinois at Chicago, USA Mayo Clinic, USA 3 University of Arizona COM and Banner-University Medical Center, USA 2
The lungs are active participants in heart failure (HF). Increases in LVEDP augments pulmonary capillary pressure (PCP) that causes fluid filtration resulting in dyspnea and, ultimately, frank pulmonary edema (PE). The increase in PCP does not translate to the severity of dyspnea indicating that more than Starling Forces contribute to the clinical manifestation of HF. Acute increases in PCP activate glycocalyx-dependent mechanotransduction resulting in oxidative stress, eNOS activation and endothelial hyperpermeability. Herein we investigated if glypican-1 (Gpc-1) contributes to pressure-dependent hyperpermeability and PE in a model of acute HF. The isolated perfused lung preparation was used to simulate acute HF in male CD-1 (wild type, WT) and glypican-1 knockout
S23
(Gpc-1-/-) mice. Control experiments were done setting left atria pressure (PLA) at 3cm H2O for 10min; acute HF was simulated by setting PLA at 10cm H2O for 10min. Lung edema was assessed by wet-to-dry ratio (W/D); reactive oxygen species (ROS) production and eNOS activation were assessed by lucigenin chemiluminescence, DHE fluorescence and immunoblotting, respectively. WT and Gpc-1-/- mice had similar increase in PA pressure (from 8 to 10 mmHg). Deletion of Gpc-1 protected mice from pressure-induced PE (W/D [acute HF and control]), respectively in WT: 7.3 70.3 vs 4.9 70.3 and in Gpc-1-/-: 4.87 0.3 vs 4.87 0.2), prevented pressure-dependent increase in ROS production in isolated membrane fraction and in total lung homogenates (15% and 80% increase in WT). eNOS activity was increased in WT (2-fold) and decreased in Gpc1-/- (0.5 fold) during acute HF. L-NIO inhibited edema development in WT (W/D 6.97 0.2 and 5.1 7 0.1 in WT and L-NIO-perfused WT, respectively). Perfusion of Gpc-1-/- lungs with NOC9 restored the response to pressure and edema development (W/D 5.1 7 0.1 and 5.78 7 0.2 in Gpc1-/- and NOC9-perfused Gpc-1-/-, respectively). Collectively, these results suggest that Gpc-1 is required for pressure-induced endothelial hyperpermeability and PE in a model of acute HF.
https://doi.org/10.1016/j.freeradbiomed.2018.10.009
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Supplementation with omega-3 fatty acids potentiates glutathione oxidation in human airway epithelial cells exposed to ozone Elizabeth Corteselli 1, n, James Samet 2 1 2
University of North Carolina at Chapel Hill, USA US EPA, USA
The health benefits of dietary fish oil consumption have been widely reported. Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, two omega-3 fatty acids found in fish oil, have been associated with anti-inflammatory and pro-resolving effects through their metabolism to specialized pro-resolving mediators (SPMs) and displacement of arachidonic acid (AA). However, the 5 and 6 double bonds in EPA and DHA respectively are targets for lipid peroxidation by ozone (O3), a major photochemical pollutant to which millions of Americans are exposed. Products of unsaturated fatty acid peroxidation by O3 have been proposed to mediate functional and inflammatory effects of O3 exposure. Thus, cellular supplementation with omega-3s has the potential to both promote and help resolve inflammation during O3 exposure. To investigate this paradox, we supplemented 16-HBE human airway epithelial cells (HAEC) expressing the fluorogenic glutathione redox potential (EGSH) sensor roGFP overnight with EPA, DHA, the monounsaturated fatty acid oleic acid (OA), or the saturated fatty acid stearic acid (SA). Alterations in EGSH were monitored in real time using live-cell microscopy during exposure to O3. We found that supplementation with EPA and DHA, but not OA or SA, caused a marked potentiation of the O3-induced increases in EGSH, evident as both an accelerated response time and increase in the magnitude of response. Notably, the potentiation of GSH oxidation occurred at O3 concentrations as low as 0.08 ppm, the current National Ambient Air Quality Standard level. These results suggest that membrane fatty acid saturation is a determinant of the oxidative responses to O3 in HAEC. These findings may have implications for dietary recommendations for populations exposed to O3. This abstract does not necessarily reflect EPA policy.
https://doi.org/10.1016/j.freeradbiomed.2018.10.010
6
Resveratrol improves endothelial function in diabetic and obese mice through SIRT1-PPARδ Wai San Cheangn University of Macau, China
SIRT1 activation reduces vascular oxidative stress, inhibits inflammatory responses, and retards cellular senescence in mouse models of diabetes. However, whether SIRT1 also plays a protective role in vascular dysfunction of diabetic and obese mice is not fully characterized. Previous work showed that PPARδ is beneficial in diabetic vascular dysfunction. Whether PPARδ is involved in the effect of SIRT1 on vascular endothelial function is unknown. We used mice with overexpression of endothelial cell-specific human SIRT1 (SIRT1-Tg) and dominant negative SIRT1 (SIRT1-mut) fed with normal chow and high fat diet to show expression of functional SIRT1 in endothelium protects against vascular dysfunction in diet-induced obese mice. Endothelial overexpression of SIRT1 improved endothelium-dependent dilation in aorta treated with risk factors including high glucose, angiotensin II, and lysophosphatidylcholine. Wild type (Ppard-wt) and PPARδ knockout (Ppard-mut) mice on high fat diet were treated with resveratrol. Resveratrol treatment improves endothelial function in Ppard-wt but not Ppard-mut mice. Experiments on isolated arteries ex vivo also showed that the effect of SIRT1 activator resveratrol or CAY10602 can be inhibited by PPARδ antagonist GSK0660. Resveratrol increased PPARδ transcriptional activity in endothelial cells. Results demonstrated here indicated that PPARδ contributes to the beneficial effect of SIRT1 against endothelial dysfunction in diabetic and obese mice. These results help to understand SIRT1-based strategy for treating vascular and metabolic dysfunction in the context of obesity and insulin resistance.
https://doi.org/10.1016/j.freeradbiomed.2018.10.008
7
Glypican-1 mediates endothelial hyperpermeability in a model of acute heart failure Andreia Chignalia 1, n, Ayman Isbatan 1, Barry Borlaug 2, Guochang Hu 1, Randal Dull 3 1
University of Illinois at Chicago, USA Mayo Clinic, USA 3 University of Arizona COM and Banner-University Medical Center, USA 2
The lungs are active participants in heart failure (HF). Increases in LVEDP augments pulmonary capillary pressure (PCP) that causes fluid filtration resulting in dyspnea and, ultimately, frank pulmonary edema (PE). The increase in PCP does not translate to the severity of dyspnea indicating that more than Starling Forces contribute to the clinical manifestation of HF. Acute increases in PCP activate glycocalyx-dependent mechanotransduction resulting in oxidative stress, eNOS activation and endothelial hyperpermeability. Herein we investigated if glypican-1 (Gpc-1) contributes to pressure-dependent hyperpermeability and PE in a model of acute HF. The isolated perfused lung preparation was used to simulate acute HF in male CD-1 (wild type, WT) and glypican-1 knockout
S23
(Gpc-1-/-) mice. Control experiments were done setting left atria pressure (PLA) at 3cm H2O for 10min; acute HF was simulated by setting PLA at 10cm H2O for 10min. Lung edema was assessed by wet-to-dry ratio (W/D); reactive oxygen species (ROS) production and eNOS activation were assessed by lucigenin chemiluminescence, DHE fluorescence and immunoblotting, respectively. WT and Gpc-1-/- mice had similar increase in PA pressure (from 8 to 10 mmHg). Deletion of Gpc-1 protected mice from pressure-induced PE (W/D [acute HF and control]), respectively in WT: 7.3 70.3 vs 4.9 70.3 and in Gpc-1-/-: 4.87 0.3 vs 4.87 0.2), prevented pressure-dependent increase in ROS production in isolated membrane fraction and in total lung homogenates (15% and 80% increase in WT). eNOS activity was increased in WT (2-fold) and decreased in Gpc1-/- (0.5 fold) during acute HF. L-NIO inhibited edema development in WT (W/D 6.97 0.2 and 5.1 7 0.1 in WT and L-NIO-perfused WT, respectively). Perfusion of Gpc-1-/- lungs with NOC9 restored the response to pressure and edema development (W/D 5.1 7 0.1 and 5.78 7 0.2 in Gpc1-/- and NOC9-perfused Gpc-1-/-, respectively). Collectively, these results suggest that Gpc-1 is required for pressure-induced endothelial hyperpermeability and PE in a model of acute HF.
https://doi.org/10.1016/j.freeradbiomed.2018.10.009
8
Supplementation with omega-3 fatty acids potentiates glutathione oxidation in human airway epithelial cells exposed to ozone Elizabeth Corteselli 1, n, James Samet 2 1 2
University of North Carolina at Chapel Hill, USA US EPA, USA
The health benefits of dietary fish oil consumption have been widely reported. Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, two omega-3 fatty acids found in fish oil, have been associated with anti-inflammatory and pro-resolving effects through their metabolism to specialized pro-resolving mediators (SPMs) and displacement of arachidonic acid (AA). However, the 5 and 6 double bonds in EPA and DHA respectively are targets for lipid peroxidation by ozone (O3), a major photochemical pollutant to which millions of Americans are exposed. Products of unsaturated fatty acid peroxidation by O3 have been proposed to mediate functional and inflammatory effects of O3 exposure. Thus, cellular supplementation with omega-3s has the potential to both promote and help resolve inflammation during O3 exposure. To investigate this paradox, we supplemented 16-HBE human airway epithelial cells (HAEC) expressing the fluorogenic glutathione redox potential (EGSH) sensor roGFP overnight with EPA, DHA, the monounsaturated fatty acid oleic acid (OA), or the saturated fatty acid stearic acid (SA). Alterations in EGSH were monitored in real time using live-cell microscopy during exposure to O3. We found that supplementation with EPA and DHA, but not OA or SA, caused a marked potentiation of the O3-induced increases in EGSH, evident as both an accelerated response time and increase in the magnitude of response. Notably, the potentiation of GSH oxidation occurred at O3 concentrations as low as 0.08 ppm, the current National Ambient Air Quality Standard level. These results suggest that membrane fatty acid saturation is a determinant of the oxidative responses to O3 in HAEC. These findings may have implications for dietary recommendations for populations exposed to O3. This abstract does not necessarily reflect EPA policy.
https://doi.org/10.1016/j.freeradbiomed.2018.10.010