The Oxidized Low-Density Lipoprotein Receptor Mediates Vascular Effects of Inhaled Vehicle Emissions

• Published in: American journal of respiratory and critical care medicine Vol. 184; no. 1; pp. 82 - 91
• Main Authors: Lund, Amie K., Lucero, JoAnn, Harman, Melissa, Madden, Michael C., McDonald, Jacob D., Seagrave, Jean Clare, Campen, Matthew J.
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.07.2011
• Subjects: Adolescent; Adult; Air Pollutants - adverse effects; Air pollution; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antibodies; Antibodies, Neutralizing - pharmacology; Aorta - metabolism; Apolipoproteins E - genetics; Atherosclerosis; Atherosclerosis - metabolism; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Diesel engines; Emissions; Endothelin-1 - metabolism; Endothelium, Vascular - metabolism; Human subjects; Humans; Intensive care medicine; Lipid Peroxidation; Lipoproteins; Lipoproteins, LDL - metabolism; Male; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mice; Mice, Knockout; Oxidative Stress; Pharmacology. Drug treatments; Plasma; Pollutants; Polymerase chain reaction; 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; Vascular disease; particulate matter; Intensive care; Atherosclerosis; Cardiovascular disease; matrix metalloproteinase; Endothelin 1; Lipoprotein; endothelin-1; oxidized low-density lipoprotein; Resuscitation; Inhalation
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201012-1967OC

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. 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. 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. 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. 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.