Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/70148
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dc.contributor.authorOu, H.C.en_US
dc.contributor.authorLee, W.J.en_US
dc.contributor.authorWu, C.M.en_US
dc.contributor.authorChen, J.F.M.en_US
dc.contributor.authorSheu, W.H.H.en_US
dc.date2012zh_TW
dc.date.accessioned2014-06-11T05:59:25Z-
dc.date.available2014-06-11T05:59:25Z-
dc.identifier.issn0741-5214zh_TW
dc.identifier.urihttp://hdl.handle.net/11455/70148-
dc.description.abstractBackground: Resistin, an adipocytokine, plays a potential role in cardiovascular disease and may contribute to increased atherosclerotic risk by modulating the activity of endothelial cells. A growing body of evidence suggests that aspirin is a potent antioxidant. We investigated whether aspirin mitigates resistin-induced endothelial dysfunction via modulation of reactive oxygen species (ROS) generation and explored the role that AMP-activated protein kinase (AMPK), a negative regulator of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, plays in the suppressive effects of aspirin on resistin-induced endothelial dysfunction. Methods: Human umbilical vein endothelial cells (HUVECs) were pretreated with various doses of aspirin (10-500 mu g/mL) for 2 hours and then incubated with resistin (100 ng/mL) for an additional 48 hours. Fluorescence produced by the oxidation of dihydroethidium (DHE) was used to quantify the production of superoxide in situ; superoxide dismutase (SOD) and catalase activities were determined by an enzymatic assay; and protein levels of AMPK-mediated downstream signaling were investigated by Western blot. Results: Treatment of HUVECs with resistin for 48 hours resulted in a 2.9-fold increase in superoxide production; however, pretreatment with aspirin resulted in a dose-dependent decrease in production of superoxide (10-500 mu g/mL; n = 3 experiments; all P<.05). Resistin also suppressed the activity of superoxide dismutase and catalase by nearly 50%; that result, however, was not observed in HUVECs that had been pretreated with aspirin at a concentration of 500 mu g/mL. The membrane translocation assay showed that the levels of NADPH oxidase subunits p47(phox) and Rac-1 in membrane fractions of HUVECs were threefold to fourfold higher in cells that had been treated with resistin for 1 hour than in untreated cells; however, pretreatment with aspirin markedly inhibited resistin-induced membrane assembly of NADPH oxidase via modulating AMPK-suppressed PKC-alpha activation. Application of AMPK alpha 1-specific siRNA resulted in increased activation of PKC-alpha and p47(phox). In addition, resistin significantly decreased AMPK-mediated downstream Akt/endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling and induced the phosphorylation of p38 mitogen-activated protein kinases, which in turn activated NF-kappa B-mediated inflammatory responses such as the release of interleukin (IL)-6 and IL-8, the overexpression of adhesion molecules, and stimulation of monocytic THP-1 cell attachment to HUVECs (2.5-fold vs control; n = 3 experiments). Furthermore, resistin downregulated eNOS and upregulated inducible NO synthase (iNOS) expression, thereby augmenting the formation of NO and protein nitrosylation. Pretreatment with aspirin, however, exerted significant cytoprotective effects in a dose-dependent manner (P<.05). Conclusions: Our findings suggest a direct connection between adipocytokines and endothelial dysfunction and provide further insight into the protective effects of aspirin in obese individuals with endothelial dysfunction. (J Vasc Surg 2012; 55: 1104-15.)en_US
dc.language.isoen_USzh_TW
dc.relationJournal of Vascular Surgeryen_US
dc.relation.ispartofseriesJournal of Vascular Surgery, Volume 55, Issue 4, Page(s) 1104-1115.en_US
dc.relation.urihttp://dx.doi.org/10.1016/j.jvs.2011.10.011en_US
dc.subjectnf-kappa-ben_US
dc.subjectactivated protein-kinaseen_US
dc.subjectnitric-oxide synthaseen_US
dc.subjectinsulin-resistanceen_US
dc.subjectmetabolic syndromeen_US
dc.subjectoxidative stressen_US
dc.subjectnad(p)hen_US
dc.subjectoxidaseen_US
dc.subjectp38 mapken_US
dc.subjectcellsen_US
dc.subjectexpressionen_US
dc.titleAspirin prevents resistin-induced endothelial dysfunction by modulating AMPK, ROS, and Akt/eNOS signalingen_US
dc.typeJournal Articlezh_TW
dc.identifier.doi10.1016/j.jvs.2011.10.011zh_TW
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