title: The oxidized low-density lipoprotein receptor mediates vascular effects of inhaled vehicle emissions.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Lovelace Respiratory Research Institute, Department of Environmental Toxicology, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA. alund@lrri.org
authors.forename: Amie K
authors.initials: AK
authors.lastname: Lund
authors.forename: JoAnn
authors.initials: J
authors.lastname: Lucero
authors.forename: Melissa
authors.initials: M
authors.lastname: Harman
authors.forename: Michael C
authors.initials: MC
authors.lastname: Madden
authors.forename: Jacob D
authors.initials: JD
authors.lastname: McDonald
authors.forename: Jean Clare
authors.initials: JC
authors.lastname: Seagrave
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campen
mesh_terms: D000293:Adolescent; D000328:Adult; D000393:Air Pollutants / Q000009:adverse effects*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D015854:Up-Regulation; D001335:Vehicle Emissions; D055815:Young Adult
chemical_list: D000393:Air Pollutants; D057134:Antibodies, Neutralizing; D001057:Apolipoproteins E; D019332:Endothelin-1; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; C495138:Olr1 protein, mouse; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D017392:Thiobarbituric Acid Reactive Substances; D001335:Vehicle Emissions; C099252:oxidized low density lipoprotein; D020780:Matrix Metalloproteinase 9