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. :
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.
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