Benzo[a]pyrene (BaP) is an environmental pollutant. Besides inducing cancers in humans, BaP has been shown to promote the development of atherosclerosis, which is the primary cause of coronary heart disease and stroke. The mechanism underlying the atherogenic action of BaP remains unknown. A currently popular theory postulates atherosclerosis as an inflammatory process driven by reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. BaP has been shown to increase intracellular ROS. Thus, the project described herein hypothesizes that generation of ROS in vascular cells is a key mechanism by which BaP promotes atherogenesis. Our laboratory has generated mouse models that overexpress Cu/Zn-superoxide dismutase (Cu/Zn-SOD) or catalase alone, or both Cu/Zn-SOD and catalase. Cu/Zn-SOD is a protein that converts superoxide to hydrogen peroxide, while catalase destroys hydrogen peroxide by converting it to water. As the relative contribution of different ROS to atherosclerosis might vary, our animal models provided a valuable tool for testing the role of superoxide and hydrogen peroxide in BaP-induced atherosclerosis. The transgenic mice overexpressing Cu/Zn-SOD and/or catalase have been crossbred into the apolipoprotein E (ApoE)-deficient mice, which spontaneously develop atherosclerotic lesions with morphological features closely resembling the atherosclerotic lesions that occur in humans. In this project, the ApoE-deficient mice, with or without overexpression of Cu/Zn-SOD and/or catalase, will be treated with BaP. We will determine: (1) whether overexpression of antioxidant enzymes inhibits BaP-induced atherogenesis and reduces the accumulation of inflammatory cells within the atherosclerotic lesions, (2) whether overexpression of antioxidant enzymes reduces BaP-induced accumulation of oxidized lipids and nitrotyrosine in the arterial wall, and (3) whether overexpression of antioxidant enzymes reduces BaP- induced atherogenic events in vascular cells, and inhibits BaP-induced gene expression and transcriptional factor activation. If our hypothesis described above is correct, BaP-induced atherosclerotic lesions will be smaller in mice overexpressing Cu/Zn-SOD and/or catalase, which will correlate to a decreased oxidative injury in the arterial wall and/or a reduced response of vascular cells to BaP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014472-04
Application #
7744697
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Nadadur, Srikanth
Project Start
2006-12-04
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2010
Total Cost
$319,413
Indirect Cost
Name
Meharry Medical College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
Lin, Xinghua; Yang, Hong; Zhang, Hongfeng et al. (2013) A novel transcription mechanism activated by ethanol: induction of Slc7a11 gene expression via inhibition of the DNA-binding activity of transcriptional repressor octamer-binding transcription factor 1 (OCT-1). J Biol Chem 288:14815-23
Okoro, Emmanuel Ugochukwu; Zhao, Yanfeng; Guo, ZhongMao et al. (2012) Apolipoprotein E4 is deficient in inducing macrophage ABCA1 expression and stimulating the Sp1 signaling pathway. PLoS One 7:e44430
Chen, Xinping; Guo, Zhongmao; Okoro, Emmanuel U et al. (2012) Up-regulation of ATP binding cassette transporter A1 expression by very low density lipoprotein receptor and apolipoprotein E receptor 2. J Biol Chem 287:3751-9
Zhang, Hong Feng; Lin, Xing Hua; Yang, Hong et al. (2012) Regulation of the Activity and Expression of Aryl Hydrocarbon Receptor by Ethanol in Mouse Hepatic Stellate Cells. Alcohol Clin Exp Res :
Prins, Petra A; Perati, Prudhvidhar R; Kon, Valentina et al. (2012) Benzo[a]pyrene potentiates the pathogenesis of abdominal aortic aneurysms in apolipoprotein E knockout mice. Cell Physiol Biochem 29:121-30
Zhou, Lichun; Yang, Hong; Lin, Xinghua et al. (2012) Cholecystokinin elevates mouse plasma lipids. PLoS One 7:e51011
Lin, Xinghua; Yang, Hong; Zhou, LiChun et al. (2011) Nrf2-dependent induction of NQO1 in mouse aortic endothelial cells overexpressing catalase. Free Radic Biol Med 51:97-106
Chen, Xinping; Zhao, Yanfeng; Guo, Zhongmao et al. (2011) Transcriptional regulation of ATP-binding cassette transporter A1 expression by a novel signaling pathway. J Biol Chem 286:8917-23
Tang, Tian; Lin, Xinghua; Yang, Hong et al. (2010) Overexpression of antioxidant enzymes upregulates aryl hydrocarbon receptor expression via increased Sp1 DNA-binding activity. Free Radic Biol Med 49:487-92
Onumah, Ogbeyalu E; Jules, George E; Zhao, Yanfeng et al. (2009) Overexpression of catalase delays G0/G1- to S-phase transition during cell cycle progression in mouse aortic endothelial cells. Free Radic Biol Med 46:1658-67

Showing the most recent 10 out of 12 publications