The overall goal of this project is to understand the mechanisms by which exposure to arsenic accelerates or aggravates atherosclerosis. Exposure to arsenic-contaminated water is a global problem and results in the manifestation of multiple cardiovascular symptoms including hypertension, stroke, and myocardial infarction. Increased atherosclerosis is likely to be the major underlying cause of the increased risk of cardiovascular disease in an arsenic-exposed population. Accordingly, the intent of this proposal is to understand the mechanism by which arsenic accelerates or exacerbates atherogenesis in a well-controlled animal model. On the basis of supportive preliminary evidence, our central hypothesis is that arsenic promotes atherogenic changes in endothelial cells and in macrophages by inducing endoplasmic reticulum (ER) stress, which in turn triggers the unfolded protein response (UPR). To test this hypothesis, we will: (1) delineate the contribution of ER stress and UPR to arsenic-mediated endothelial cell and macrophage activation;(2) examine the progression of atherogenesis in arsenic-exposed mice;and (3) elucidate the role of UPR in exacerbation of atherogenesis by arsenic. To accomplish these aims, we will examine whether exposure to arsenic induces ER stress and triggers UPR in endothelial cells and macrophages. We will identify which aspects of the UPR are triggered by arsenic and whether ER stress contributes to arsenic-induced activation of endothelial cells and foam cell formation. To assess how arsenic affects atherogenesis, we will examine early, intermediate, and advanced lesions for lipid accumulation, cellularity, inflammation, and oxidative stress in apoE-null mice exposed to arsenic. Bone marrow transplants from arsenic-exposed to non-exposed mice will be performed to delineate the specific contribution of macrophages to arsenic toxicity. To identify the in vivo role of UPR in arsenic toxicity, we will examine which components of ER stress and UPR are activated in the lesions of arsenic-exposed animals, and whether inhibition of the adaptive phase of UPR by deleting the ATF3 gene accelerates or treatment with chemical chaperones of protein folding inhibits lesion formation. Results of this project may lead to a better understanding of the mechanisms by which arsenic affects atherogenesis and how they could be therapeutically prevented.

Public Health Relevance

Large sections of human population in the US as well as Asia are exposed to high levels of arsenic in drinking water. Previous epidemiological studies show that people exposed to high levels of arsenic have a higher risk of developing cardiovascular disease. Nevertheless, the mechanisms by which arsenic elevates cardiovascular disease risk are not known. This project is designed to mimic human exposures to arsenic in an animal model and test whether exposure to arsenic increases the rate and/or the extent of atherosclerotic lesion formation in atherosclerosis-prone mice. The project seeks to understand the underlying molecular mechanisms by which arsenic increases atherosclerosis;which processes are affected;and which cellular and molecular mechanisms mediate the cardiovascular toxicity of arsenic. Results obtained from this project are likely to provide novel models for testing atherogenic effects of arsenic exposure, in developing a better understanding of how arsenic worsens atherosclerosis and how the atherogenic effects of arsenic could be ameliorated and treated.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DIG-C (90))
Program Officer
Nadadur, Srikanth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Louisville
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Barski, Oleg A; Xie, Zhengzhi; Baba, Shahid P et al. (2013) Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 33:1162-70
Vladykovskaya, Elena; Sithu, Srinivas D; Haberzettl, Petra et al. (2012) Lipid peroxidation product 4-hydroxy-trans-2-nonenal causes endothelial activation by inducing endoplasmic reticulum stress. J Biol Chem 287:11398-409
Vladykovskaya, Elena; Ozhegov, Evgeny; Hoetker, J David et al. (2011) Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids. J Lipid Res 52:2209-25
Conklin, Daniel J; Prough, Russell A; Juvan, Peter et al. (2011) Acrolein-induced dyslipidemia and acute-phase response are independent of HMG-CoA reductase. Mol Nutr Food Res 55:1411-22
Srivastava, Sanjay; Sithu, Srinivas D; Vladykovskaya, Elena et al. (2011) Oral exposure to acrolein exacerbates atherosclerosis in apoE-null mice. Atherosclerosis 215:301-8
Conklin, Daniel J; Barski, Oleg A; Lesgards, Jean-Francois et al. (2010) Acrolein consumption induces systemic dyslipidemia and lipoprotein modification. Toxicol Appl Pharmacol 243:1-12
Srivastava, Sanjay; Ramana, Kota V; Bhatnagar, Aruni et al. (2010) Synthesis, quantification, characterization, and signaling properties of glutathionyl conjugates of enals. Methods Enzymol 474:297-313
Sithu, Srinivas D; Srivastava, Sanjay; Siddiqui, Maqsood A et al. (2010) Exposure to acrolein by inhalation causes platelet activation. Toxicol Appl Pharmacol 248:100-10
Srivastava, Sanjay; Vladykovskaya, Elena; Barski, Oleg A et al. (2009) Aldose reductase protects against early atherosclerotic lesion formation in apolipoprotein E-null mice. Circ Res 105:793-802
Srivastava, Sanjay; Vladykovskaya, Elena N; Haberzettl, Petra et al. (2009) Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE-/- mice. Toxicol Appl Pharmacol 241:90-100

Showing the most recent 10 out of 12 publications