Methylglyoxal-induced increase in peroxynitrite and inflammation related to diabetes
| dc.contributor.advisor | Wu, Lingyun | en_US |
| dc.creator | Wang, Hui | en_US |
| dc.date.accessioned | 2009-06-24T15:15:07Z | en_US |
| dc.date.accessioned | 2013-01-04T04:40:31Z | |
| dc.date.available | 2010-06-29T08:00:00Z | en_US |
| dc.date.available | 2013-01-04T04:40:31Z | |
| dc.date.created | 2009 | en_US |
| dc.date.issued | 2009 | en_US |
| dc.date.submitted | 2009 | en_US |
| dc.description.abstract | Methylglyoxal (MG) is a reactive α-oxoaldehyde and a glucose metabolite. Previous studies in our laboratory have shown that MG induces the production of reactive oxygen species (ROS), such as superoxide (O₂˙¯), nitric oxide (NO) and peroxynitrite (ONOO¯), in vascular smooth muscle cells (VSMCs, A-10 cells). However, the effect of endogenous MG and mechanisms of MG-induced oxidative stress have not been thoroughly explored. The present study investigated fructose (a precursor of MG)- induced ONOO¯ formation in A-10 cells and whether this process was mediated via endogenous MG formation; roles of MG in regulating mitochondrial ROS (mtROS) production and mitochondrial functions in A-10 cells; and effect of MG on neutrophils in patients with type 2 diabetes mellitus (T2DM). Fructose induced intracellular production of MG in a concentration- and time- dependent manner. A significant increase in the production of NO, O₂˙¯, and ONOO¯ was observed in the cells exposed to fructose or MG. Fructose- or MG-induced ONOO¯ generation was significantly inhibited by MG scavengers and by O₂˙¯ or NO inhibitors. The data showed that fructose treatment increased the formation of ONOO¯ via increased NO and O₂˙¯ production in A-10 cells, and this effect was directly mediated by an elevated intracellular concentration of MG. By inhibiting complex III and manganese superoxide dismutase activities, MG induced mitochondrial overproduction of O₂˙¯, and mitochondrial ONOO¯ further. MG also reduced mitochondrial ATP synthesis, indicating the dysfunction of mitochondria. In addition, MG increased plasma NO levels in patients with T2DM, which reflected the oxidative status in those patients. MG-induced oxidative stress in patients with T2DM significantly enhanced levels of cytokines released from neutrophils. Moreover, the neutrophils from T2DM patients showed a greater proclivity for apoptosis, which was further increased by in vitro MG treatment. Our data demonstrate that MG-induced oxidative damage, particularly ONOO¯ production, contributes to the pathogenesis of T2DM and its vascular complications. | en_US |
| dc.identifier.uri | http://hdl.handle.net/10388/etd-06242009-151507 | en_US |
| dc.language.iso | en_US | en_US |
| dc.subject | Peroxynitrite | en_US |
| dc.subject | Methylglyoxal | en_US |
| dc.subject | Mitochondria | en_US |
| dc.subject | Type 2 diabetes | en_US |
| dc.subject | Smooth muscle cell | en_US |
| dc.title | Methylglyoxal-induced increase in peroxynitrite and inflammation related to diabetes | en_US |
| dc.type.genre | Thesis | en_US |
| dc.type.material | text | en_US |
| thesis.degree.department | Pharmacology | en_US |
| thesis.degree.discipline | Pharmacology | en_US |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) | en_US |