Atherosclerosis is a major cause of morbidity and mortality. Oxidative stress has been strongly implicated in the pathogenesis of atherosclerosis, but few studies have addressed the mechanisms by which the vascular wall defends against oxidant, or electrophilic, injury. Our recent data show that a specific subtype of glutathione S-transferase (GST), GST A4-4, is selectively induced in vascular smooth muscle cells (VSMCs) of rat aorta in response to electrophilic injury caused by alpha, beta-unsaturated aldehydes such as acrolein, 4-hydroxynonenal (4-HNE) and 4-hydroxyhexenal (4-HHE), which are toxic end products of lipid peroxidation implicated in the pathogenesis of atherosclerosis. Our recent data in human tissue also supports a role for HGST A4-4 in the pathogenesis of atherosclerosis. Our recent data in human tissue also supports a role for HGST A4-4 in the atherosclerotic plaque. Our hypothesis is that the human vascular GST isozyme, HGST A4-4, functions in the cell's defense against highly reactive alpha, beta- unsaturated aldehydes that are toxic end products of lipid peroxidation, and are implicated in the pathogenesis of atherosclerosis. We expect hGST A4-4 is induced in vascular smooth muscle cells (VSMC) and endothelium during development of the early human atherosclerotic plaque in response to oxidative stress. By manipulating this enzyme in cultured vascular cells from rat, and in genetically altered in vivo mouse models (GST-/-; apoE-/-; a double knock of apoE and GST) we will be able to alter the course of oxidative injury and atherogenesis. Using human blood vessels , our Specific Aim #1 will determine if HGST 4-4 induction and accumulation of suspected aldehyde/aldehyde adducts are early markers of oxidative injury in the early or """"""""fibrous"""""""" human atherosclerotic plaque.
In Specific Aim #2, we will utilize already- developed rat VSMC, and endothelial cells made resistant to alpha, beta- unsaturated aldehydes, to examine the role of GST during oxidative/atherosclerotic stress.
In Specific Aim #3 we will use a recently developed genetically altered mouse GST during oxidative/atherosclerotic stress.
In Specific Aim #3 we will use a recently developed genetically altered mouse GST knockout of GST and apoE, to manipulate GST A4-4 in order to worsen/hasten the development of atherosclerosis. These studies will focus on early events during oxidative damage and defense mechanisms in the vascular wall, so that therapeutic strategies to prevent initiation and propagation of the atherosclerotic plaque may be devised.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065416-05
Application #
7030963
Study Section
Pathology A Study Section (PTHA)
Program Officer
Srinivas, Pothur R
Project Start
2002-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$290,997
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Salabei, Joshua K; Balakumaran, Arun; Frey, Justin C et al. (2012) Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy. Toxicol Appl Pharmacol 262:265-72
Xu, Ya; Gong, Bin; Yang, Yongzhen et al. (2010) Adenovirus-mediated overexpression of glutathione-s-transferase mitigates transplant arteriosclerosis in rabbit carotid allografts. Transplantation 89:409-16
Xu, Y; Gong, B; Yang, Y et al. (2007) Glutathione-S-transferase protects against oxidative injury of endothelial cell tight junctions. Endothelium 14:333-43
Gong, Bin; Boor, Paul J (2006) The role of amine oxidases in xenobiotic metabolism. Expert Opin Drug Metab Toxicol 2:559-71
Conklin, D J; Bhatnagar, A; Cowley, H R et al. (2006) Acrolein generation stimulates hypercontraction in isolated human blood vessels. Toxicol Appl Pharmacol 217:277-88
Dwivedi, Seema; Sharma, Rajendra; Sharma, Abha et al. (2006) The course of CCl4 induced hepatotoxicity is altered in mGSTA4-4 null (-/-) mice. Toxicology 218:58-66
Wang, Liansheng; Yang, Yongzhen; Dwivedi, Seema et al. (2006) Manipulating glutathione-S-transferases may prevent the development of tolerance to nitroglycerin. Cardiovasc Toxicol 6:131-44
Boor, Paul J; Yang, Yonzhen; Gong, Bin (2006) Role of the media in vascular injury: atherosclerosis and dissection. Toxicol Pathol 34:33-8
Conklin, D J; Cowley, H R; Wiechmann, R J et al. (2004) Vasoactive effects of methylamine in isolated human blood vessels: role of semicarbazide-sensitive amine oxidase, formaldehyde, and hydrogen peroxide. Am J Physiol Heart Circ Physiol 286:H667-76
Yang, Yongzhen; Yang, Yusong; Trent, Margaret B et al. (2004) Glutathione-S-transferase A4-4 modulates oxidative stress in endothelium: possible role in human atherosclerosis. Atherosclerosis 173:211-21

Showing the most recent 10 out of 13 publications