MSpace at the University of Manitoba >
Faculty of Graduate Studies (Electronic Theses and Dissertations) >
FGS - Electronic Theses & Dissertations (Public) >
Please use this identifier to cite or link to this item:
|Title: ||Mechanisms for Oxidized or Glycated LDL-induced Oxidative Stress and Upregulation of Plasminogen Activator Inhibitor-1 in Vascular Cells.|
|Authors: ||Sangle, Ganesh|
|Supervisor: ||Shen, Garry (Internal Medicine)|
|Examining Committee: ||Halayko, Andrew (Physiology) Nyomba, Gregoire (Internal Medicine) Moghadasian, Mohammed (Human Nutritional Sciences) Chakrabarti, Subrata (University of Western Ontario)|
|Graduation Date: ||October 2010|
|Keywords: ||Plasminogen activator inhibitor-1|
|Issue Date: ||13-Sep-2010|
|Abstract: ||Atherosclerotic 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.|
|Appears in Collections:||FGS - Electronic Theses & Dissertations (Public)|
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.