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Title: The oxidized low-density lipoprotein receptor mediates vascular effects of inhaled vehicle emissions.

Authors: Lund, Amie K; Lucero, JoAnn; Harman, Melissa; Madden, Michael C; McDonald, Jacob D; Seagrave, Jean Clare; Campen, Matthew J

Published In Am J Respir Crit Care Med, (2011 Jul 01)

Abstract: RATIONALE: To determine vascular signaling pathways involved in inhaled air pollution (vehicular engine emission) exposure-induced exacerbation of atherosclerosis that are associated with onset of clinical cardiovascular events. OBJECTIVES: To elucidate the role of oxidized low-density lipoprotein (oxLDL) and its primary receptor on endothelial cells, the lectin-like oxLDL receptor (LOX-1), in regulation of endothelin-1 expression and matrix metalloproteinase activity associated with inhalational exposure to vehicular engine emissions. METHODS: Atherosclerotic apolipoprotein E knockout mice were exposed by inhalation to filtered air or mixed whole engine emissions (250 μg particulate matter [PM]/m(3) diesel + 50 μg PM/m(3) gasoline exhausts) 6 h/d for 7 days. Concurrently, mice were treated with either mouse IgG or neutralizing antibodies to LOX-1 every other day. Vascular and plasma markers of oxidative stress and expression proatherogenic factors were assessed. In a parallel study, healthy human subjects were exposed to either 100 μg PM/m(3) diesel whole exhaust or high-efficiency particulate air and charcoal-filtered "clean" air (control subjects) for 2 hours, on separate occasions. MEASUREMENTS AND MAIN RESULTS: Mixed emissions exposure increased oxLDL and vascular reactive oxygen species, as well as LOX-1, matrix metalloproteinase-9, and endothelin-1 mRNA expression and also monocyte/macrophage infiltration, each of which was attenuated with LOX-1 antibody treatment. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma-soluble LOX-1. CONCLUSIONS: These findings demonstrate that acute exposure to vehicular source pollutants results in up-regulation of vascular factors associated with progression of atherosclerosis, endothelin-1, and matrix metalloproteinase-9, mediated through oxLDL-LOX-1 receptor signaling, which may serve as a novel target for future therapy.

PubMed ID: 21493736 Exiting the NIEHS site

MeSH Terms: Adolescent; Adult; Air Pollutants/adverse effects*; Animals; Antibodies, Neutralizing/pharmacology; Aorta/metabolism*; Apolipoproteins E/genetics; Atherosclerosis/metabolism; Endothelin-1/metabolism; Endothelium, Vascular/metabolism; Humans; Lipid Peroxidation; Lipoproteins, LDL/metabolism; Male; Matrix Metalloproteinase 9/metabolism; Mice; Mice, Knockout; Oxidative Stress; Reactive Oxygen Species/metabolism; Scavenger Receptors, Class E/blood; Scavenger Receptors, Class E/immunology; Scavenger Receptors, Class E/metabolism*; Signal Transduction; Thiobarbituric Acid Reactive Substances/metabolism; Up-Regulation; Vehicle Emissions*; Young Adult

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