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

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.

• Authors: Amie K Lund, JoAnn Lucero, Melissa Harman, Michael C Madden, Jacob D McDonald, Jean Clare Seagrave, Matthew J Campen
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 184 Issue 1 Pg. 82-91 (Jul 01 2011) ISSN: 1535-4970 [Electronic] United States
• PMID: 21493736 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Air Pollutants
• Antibodies, Neutralizing
• Apolipoproteins E
• Endothelin-1
• Lipoproteins, LDL
• OLR1 protein, human
• Olr1 protein, mouse
• Reactive Oxygen Species
• Scavenger Receptors, Class E
• Thiobarbituric Acid Reactive Substances
• Vehicle Emissions
• oxidized low density lipoprotein
• Matrix Metalloproteinase 9

Topics

• 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, immunology, metabolism)
• Signal Transduction
• Thiobarbituric Acid Reactive Substances (metabolism)
• Up-Regulation
• Vehicle Emissions
• Young Adult