Although epidemiological studies have shown a clear link between pollution and cardiovascular events, the pathophysiologic mechanisms remain poorly characterized. There is emerging evidence that particulate components of air pollution (PM10 as well as PM2.5) may mediate organ toxicity through generation of reactive oxygen species (ROS). Since pollution mediated adverse cardiovascular outcomes seem to preferentially target at-risk patient populations with pre-existing risk factors and established cardiovascular diseases (all associated with heightened oxidant stress), studies of pollution exposure in susceptible animal models is likely to provide realistic insights into relevant pathologic mechanisms. The overall hypothesis of this study is that long-term exposure to environmentally relevant concentrations of concentrated airborne particulate substances (CAPS) plays a fundamental role in the initiation and progression of atherosclerosis in a genetically susceptible model (Apo E-/-) through the activation of ROS dependent pathways. In the first specific aim, the investigators hypothesize that sub-acute exposure to CAPS results in early deterioration in endothelial function through the generation of superoxide in the vessel wall, that results in the inactivation of bio-available nitric oxide. This will be accomplished by studying the effects of a sub-acute (6-week) exposure to CAPS on endothelium dependent responses, free-radical sources in the vasculature and investigating the effects of CAPS on nitric oxide synthase activity and cGMP levels in the vessel wall. In the second specific aim they will elucidate the effects of sub-acute (6 week) and chronic (20 week) CAPS exposure on vascular inflammation and atherosclerosis using histochemical, immunohistochemical and magnetic resonance microscopy (MRM) approaches. In the final specific aim, the investigators will investigate potential mechanisms through which CAPS may modulate eNOS function in the vessel wall and will evaluate the effect of CAP on the eNOS cofactor vascular 6R-5,6,7,8-tetrahydrobiopterin (BH4) and its oxidized analogs [7,8 dihydrobiopterin (BH2) and biopterin] in arterial segments derived from Apo E-/- exposed to CAPS. Principal component analysis will be performed to elucidate which source-related components are most closely associated with biological responses in specific aims 1 and 2. This study is expected to provide a firm linkage between CAPS exposure and atherosclerosis progression and will provide a pathophysiologic basis for the adverse cardiovascular effects of CAPS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013406-05
Application #
7269374
Study Section
Special Emphasis Panel (ZES1-LKB-E (CA))
Program Officer
Nadadur, Srikanth
Project Start
2004-08-06
Project End
2008-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
5
Fiscal Year
2007
Total Cost
$276,356
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Ying, Zhekang; Chen, Minjie; Xie, Xiaoyun et al. (2016) Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling. PLoS One 11:e0148305
Ying, Zhekang; Allen, Katryn; Zhong, Jixin et al. (2016) Subacute inhalation exposure to ozone induces systemic inflammation but not insulin resistance in a diabetic mouse model. Inhal Toxicol 28:155-63
Ying, Zhekang; Xie, Xiaoyun; Chen, Minjie et al. (2015) Alpha-lipoic acid activates eNOS through activation of PI3-kinase/Akt signaling pathway. Vascul Pharmacol 64:28-35
Ying, Zhekang; Xie, Xiaoyun; Bai, Yuntao et al. (2015) Exposure to concentrated ambient particulate matter induces reversible increase of heart weight in spontaneously hypertensive rats. Part Fibre Toxicol 12:15
Rao, Xiaoquan; Zhong, Jixin; Maiseyeu, Andrei et al. (2014) CD36-dependent 7-ketocholesterol accumulation in macrophages mediates progression of atherosclerosis in response to chronic air pollution exposure. Circ Res 115:770-780
Ying, Zhekang; Xu, Xiaohua; Bai, Yuntao et al. (2014) Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation. Environ Health Perspect 122:79-86
Ying, Zhekang; Xu, Xiaohua; Chen, Minjie et al. (2013) A synergistic vascular effect of airborne particulate matter and nickel in a mouse model. Toxicol Sci 135:72-80
Ying, Zhekang; Kampfrath, Thomas; Sun, Qinghua et al. (2011) Evidence that ?-lipoic acid inhibits NF-?B activation independent of its antioxidant function. Inflamm Res 60:219-25
Kampfrath, Thomas; Maiseyeu, Andrei; Ying, Zhekang et al. (2011) Chronic fine particulate matter exposure induces systemic vascular dysfunction via NADPH oxidase and TLR4 pathways. Circ Res 108:716-26
Reichert, Barbara; Yasmeen, Rumana; Jeyakumar, Shanmugam M et al. (2011) Concerted action of aldehyde dehydrogenases influences depot-specific fat formation. Mol Endocrinol 25:799-809

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