Abstract 5814: Vascular Lectin-Like-OxLDL Scavenger Receptor (LOX-1) Mediates Oxidative Stress, Endothelin-1, and Matrix Metalloproteinase Expression in the Vasculature of Vehicular Engine Emissions-Exposed Mice

Abstract

A positive correlation between exposure to traffic-related air pollution and increased rates of cardiovascular morbidity and mortality has been well documented; however, underlying mechanisms have not yet been elucidated. We have reported that vascular oxidative stress levels are significantly elevated in atherosclerotic apolipoprotein KO (ApoE−/−) mice exposed to vehicular emissions, which appears to mediate increases in vascular matrix metalloproteinases (MMPs) and endothelin-1 (ET-1), expression of which are associated with progression of atherosclerosis. Since ROS production promotes formation of oxidized LDL (oxLDL), we investigated whether the effects of oxLDL on the vasculature, in response to exposure to vehicular emissions, are mediated via the lectin-like-ox-LDL receptor (LOX-1). To test this hypothesis, 10 wk old male ApoE−/− mice on a high fat diet received either mouse IgG (control, 16 μ g protein/ml, 0.1 ml/mouse, i.p.) or the neutralizing antibodies to LOX-1 (anti-mouse LOX-1/SR-E1 antibody: 16 μ g protein/ml, 0.1 ml/mouse, i.p.) every other day. Mice were randomly assigned to inhalational exposure of either filtered-air (FA: n=12 anti-LOX-1, n=12 IgG) or a mixed exposure of 250 μ g PM/m 3 diesel exhaust + 50 μ g PM/m 3 gasoline engine exhaust (n=12 anti-LOX-1, n=12 IgG) for 6 hr/day for 7 days. Analysis showed significant elevations in oxLDL and aorta oxidative stress from mice exposed to vehicular exhaust compared to FA. Anti-LOX-1 treatment ameliorated the increase in circulating oxLDL, as well as vascular lipid peroxidation in vehicular exhaust-exposed animals. Aorta LOX-1, ET-1, MMP-9 and tissue inhibitor of MMPs, TIMP-1 and -2 mRNA expression, as well as MMP-9 protein and activity, were also observed to be significantly elevated with exposure to mixed vehicular exhaust, of which LOX-1, ET-1 and MMP-9 were attenuated through LOX-1 Ab treatment. In agreement with LOX-1 mRNA findings, LOX-1 protein and soluble LOX-1 (sLOX-1) plasma levels were also found increased in exposure animals. Such findings indicate that effects of ROS (and oxLDL), as well as expression of vascular factors associated with progression of atherosclerosis (ET-1 and MMPs), induced by vehicular exhaust exposure, are likely mediated through the LOX-1 receptor.