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dc.contributor.supervisorShen, Garry (Internal Medicine)en
dc.contributor.authorSangle, Ganesh
dc.date.accessioned2010-09-13T15:06:03Z
dc.date.available2010-09-13T15:06:03Z
dc.date.issued2010-09-13T15:06:03Z
dc.identifier.urihttp://hdl.handle.net/1993/4185
dc.description.abstractAtherosclerotic cardiovascular disease is the leading cause of death of adults in North America. Diabetes is a classical risk factor for atherosclerotic cardiovascular disease. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of fibrinolysis. Elevated levels of PAI-1, oxidized low-density lipoprotein (oxLDL) and glycated LDL (glyLDL) were detected in patients with diabetes. Increased oxidative stress is associated with diabetic cardiovascular complications. Previous studies in our laboratory demonstrated that oxLDL or glyLDL increased the production of PAI-1 or reactive oxygen species (ROS) in vascular endothelial cells (EC). This study was undertaken to investigate transmembrane signaling mechanisms involved in oxLDL or glyLDL-induced upregulation of PAI-1 in cultured vascular EC. Further, we examined the mechanism for oxLDL or glyLDL-induced oxidative stress in EC. The results of the present studies demonstrated novel transmembrane signaling pathway for oxLDL-induced PAI-1 production in vascular EC. We demonstrated that lectin-like oxLDL receptor-1, H-Ras, a small G-protein and Raf-1/ERK-1/2 mediate oxLDL-induced PAI-1 expression in cultured EC. GlyLDL may activate EC via a distinct transmembrane signaling pathway. The results of the present study demonstrated that receptor for advanced glycation end products, NADPH oxidase and H-Ras/Raf-1 are implicated in the upregulation of heat shock factor-1 or PAI-1 in vascular EC under diabetes-associated metabolic stress. We investigated the effects of oxLDL or glyLDL on mitochondrial function in EC. Treatment with oxLDL or glyLDL significantly impaired the activities of electron transport chain (ETC) enzymes and also increased mitochondria-associated ROS in EC. The findings suggest that oxLDL or glyLDL attenuated activity of ETC and increased ROS generation in EC, which potentially contributes to oxidative stress in vasculature. In conclusion, diabetes-associated lipoproteins may upregulate stress response mediators and PAI-1 production via distinct transmembrane signaling pathways. OxLDL or glyLDL may increase ROS production via NOX activation and the impairment of mitochondrial ETC enzyme activity in EC. The understanding and identification of the regulatory mechanisms involved in diabetes-associated lipoprotein-induced signaling may help pharmacological design for the management of diabetic cardiovascular complications.en
dc.format.extent1771760 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectPlasminogen activator inhibitor-1en
dc.subjectAtherosclerosisen
dc.subjectglycated LDLen
dc.subjectoxidized LDLen
dc.subjectdiabetesen
dc.titleMechanisms for Oxidized or Glycated LDL-induced Oxidative Stress and Upregulation of Plasminogen Activator Inhibitor-1 in Vascular Cells.en
dc.typedoctoral thesisen_US
dc.degree.disciplinePhysiologyen_US
dc.contributor.examiningcommitteeHalayko, Andrew (Physiology) Nyomba, Gregoire (Internal Medicine) Moghadasian, Mohammed (Human Nutritional Sciences) Chakrabarti, Subrata (University of Western Ontario)en
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.noteOctober 2010en


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