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Author Whalin, Matthew K
Title Investigating the role of advanced glycation endproducts and the NADPH oxidase in diabetic vascular disease
book jacket
Descript 100 p
Note Source: Dissertation Abstracts International, Volume: 69-04, Section: B, page: 2257
Adviser: W. Robert Taylor
Thesis (Ph.D.)--Emory University, 2008
The formation of advanced glycation endproducts (AGEs) and the production of reactive oxygen species (ROS) are two mechanisms by which diabetes mellitus may induce a pro-inflammatory state and lead to the development of cardiovascular disease. This dissertation recounts two studies designed to test the ability of AGEs to produce ROS and stimulate the expression of pro-inflammatory genes in the vasculature. The first study examined the role of AGEs in inducing the expression of the protein subunits of the NADPH oxidase, a major source of ROS in blood vessels. AGEs activated the NADPH oxidase to produce ROS in the aortas of mice. Treatment with AGEs, both in vivo and ex vivo, also induced aortic expression of many of the same NADPH oxidase subunits which were observed in diabetic mice. This represents the first evidence of AGEs as a mediator of the increased levels of NADPH oxidase proteins which have been observed in diabetic animals and humans. The second study examined the role of NADPH oxidase activation in mediating the induction of pro-inflammatory genes by AGEs
Administration of AGEs to mice stimulated aortic expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1), two proteins which are increased in the vasculature of patients with diabetes. Apocynin, an inhibitor of NADPH oxidase activation, blocked the AGE-mediated increase in VCAM-1 and MCP-1. The same inhibition occurred in isolated endothelial and vascular smooth muscle cells. The studies of mouse aortic tissue provide a link between clinical studies of diabetes and cell culture studies of AGE effects. Together, these studies suggest a role for AGE-mediated NADPH oxidase activation in the promotion of inflammation in the diabetic vasculature. A key implication of this work is that the AGE signaling pathway and the NADPH oxidase represent important therapeutic targets for the treatment of diabetic vascular disease
School code: 0665
DDC
Host Item Dissertation Abstracts International 69-04B
Subject Health Sciences, Pharmacology
Health Sciences, Medicine and Surgery
Biology, Physiology
0419
0564
0719
Alt Author Emory University
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