MMP-9 Activity Mediates Vascular Effects of Inhaled Environmental Air Pollutants

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DESCRIPTION (provided by applicant) Atherosclerosis, an inflammatory 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 incidence; however the cellular pathways involved are unknown. Remodeling of arterial extracellular matrix (ECM) is a crucial step in the progression of atherosclerosis, which is primarily regulated through matrix metalloproteinase (MMP) activity. The investigators have reported elevated vascular MMP-9 associated with inhalational exposure to gasoline 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, gasoline engine emissions (GEE), 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, the investigators will utilize atherosclerosis-prone ApoE knockout mice. In Aim 1, they will investigate the molecular pathways involved in ET-1-mediated expression of vascular MMP-9, and regulation of MMP tissue inhibitors (TIMPs), following exposure to GEE, through use of an ET-1receptor antagonist (BQ-123) and a MMP inhibitor, respectively. Resulting MAPK pathway ERK1/2, p38, and JNK expression will be analyzed. In Aim 2, they will determine whether GEE results in elevated ET-1and 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, the investigators 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 GEE by anti-LOX-1 antibody expression knockdown. In Aim 4, they will determine whether exposure to common environmental air pollutants (GEE, diesel exhaust, wood-smoke) results in expression of circulating biomarkers, MMP-9 and soluble LOX-1, in murine and human samples. Relevance: Considering the overwhelming burden of atherosclerosis, AMI, and stroke on healthcare today, it is critical to identify environmental factors and molecular pathways involved in the initiation and/or progression of such diseases, which may serve as targets for therapy.