Atherosclerosis, an Inflamniatory disease associated with the production of arterial plaques, is the leading cause of morbidity and mortality worldwide. Plaque rupture commonly leads to clinical outcomes such as stroke or acute myocardial infarction (AMI). Substantial epidemiological evidence indicates that particulate and gaseous air pollutants are associated with increased rates of cardiovascular incidents, however the cellular pathways involved have not yet been elucidated. Remodeling of arterial extracellular matrix (ECM) is a crucial step in the progression of atherosclerosis, which is primarily regulated through matrix metalloproteinase (MMP) activity. We have reported elevated vascular MMP-9 associated with inhaiational exposure to vehicular exhaust, however regulation of MMP-9 in this model has not been elucidated. The goal of this proposal is to test the hypothesis that exposure to the ubiquitous environmental air pollutant, vehicular engiiie emissions (VEE), results in oxidized lipoprotein (oxLDL)-mediated induction of endothelin-1 (ET-1) and activation of vascular and circulating MMP-9 through an ET-1 - ETA mitogen activated protein kinase (MAPK) signaling pathway. For the experiments proposed, we will utilize atherosclerosis-prone ApoE knockout mice.
In Aim 1, we will investigate Ihe molecular pathways involved in ET-1-mediated expression of vascular MMP-9, and regulation of MMP tissue inhibitors (TIMPs), following exposure to VEE, through use of an ET-1 receptor antagonist (BQ-123) and a MMP inihibitor, respectively. Resulting MAPK pathway ERK1/2, p38, and JNK expression will be analyzed.
In Aim 2, we wili detennine whether VEE results in elevated ET-1 and MMP-9 in the coronary and cerebrovasculature with BQ-123 treatment. MMP-9 and TIMP expression, and cellular localization will be analyzed.
In Aim 3, we. will elucidate the role of oxLDL signaling, via lectin-like oxLDL receptor (LOX-1), in regulating induction .of ET-1 and MMP9, in response to exposure to VEE by anti-LOX-1 antibody expression knockdown^ In Aim 4, we will deterrnine whether exposure to common environmental air pollutants (VEE,: mixed gasolinerand diesel exhaust) results in expression of circulating biomarkers, MMP-S and soluble LOX-1, in murine and-human samples. :

Public Health Relevance

Considering the ovenvhelming burden of atherosclerosis, heart attack, and stroke on'^health.care today, it is Imperative to identify environmental fectors, as well as the underlying cellular and molecular pathways they regulate, involved in the initiation and/or progression of such disease states. Identification of these factors (biomarkers) may allow them to serve as targets for future therapies, thereby improving clinical outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Transition Award (R00)
Project #
4R00ES016586-02
Application #
7916962
Study Section
Special Emphasis Panel (NSS)
Program Officer
Nadadur, Srikanth
Project Start
2009-09-01
Project End
2012-07-31
Budget Start
2009-09-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$249,000
Indirect Cost
Name
Lovelace Biomedical & Environmental Research
Department
Type
DUNS #
045911138
City
Albuquerque
State
NM
Country
United States
Zip Code
87108
Davis, Griffith; Lucero, JoAnn; Fellers, Caitlin et al. (2018) The effects of subacute inhaled multi-walled carbon nanotube exposure on signaling pathways associated with cholesterol transport and inflammatory markers in the vasculature of wild-type mice. Toxicol Lett 296:48-62
Suwannasual, Usa; Lucero, JoAnn; McDonald, Jacob D et al. (2018) Exposure to traffic-generated air pollutants mediates alterations in brain microvascular integrity in wildtype mice on a high-fat diet. Environ Res 160:449-461
Lucero, JoAnn; Suwannasual, Usa; Herbert, Lindsay M et al. (2017) The role of the lectin-like oxLDL receptor (LOX-1) in traffic-generated air pollution exposure-mediated alteration of the brain microvasculature in Apolipoprotein (Apo) E knockout mice. Inhal Toxicol 29:266-281
Campen, Matthew; Robertson, Sarah; Lund, Amie et al. (2014) Engine exhaust particulate and gas phase contributions to vascular toxicity. Inhal Toxicol 26:353-60
Duan, Ming; Yao, Honghong; Hu, Guoku et al. (2013) HIV Tat induces expression of ICAM-1 in HUVECs: implications for miR-221/-222 in HIV-associated cardiomyopathy. PLoS One 8:e60170
Oppenheim, Hannah A; Lucero, JoAnn; Guyot, Anne-C├ęcile et al. (2013) Exposure to vehicle emissions results in altered blood brain barrier permeability and expression of matrix metalloproteinases and tight junction proteins in mice. Part Fibre Toxicol 10:62
Lund, Amie K; Doyle-Eisele, Melanie; Lin, Ying-Hsuan et al. (2013) The effects of ?-pinene versus toluene-derived secondary organic aerosol exposure on the expression of markers associated with vascular disease. Inhal Toxicol 25:309-24
Campen, Matthew J; Lund, Amie; Rosenfeld, Michael (2012) Mechanisms linking traffic-related air pollution and atherosclerosis. Curr Opin Pulm Med 18:155-60
Kodavanti, Urmila P; Thomas, Ronald; Ledbetter, Allen D et al. (2011) Vascular and cardiac impairments in rats inhaling ozone and diesel exhaust particles. Environ Health Perspect 119:312-8
Lund, Amie K; Lucero, JoAnn; Harman, Melissa et al. (2011) The oxidized low-density lipoprotein receptor mediates vascular effects of inhaled vehicle emissions. Am J Respir Crit Care Med 184:82-91

Showing the most recent 10 out of 11 publications