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The oxidized low-density lipoprotein receptor mediates vascular effects of inhaled vehicle emissions
Citation:
Lund, A., J. Lucero, M. Harman, M. C. MADDEN, J. Seagrave, J. D. McDonald, AND M. Campen. The oxidized low-density lipoprotein receptor mediates vascular effects of inhaled vehicle emissions. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. American Thoracic Society, New York, NY, 184(1):82-91, (2011).
Impact/Purpose:
To determine vascular signaling pathways involved in air pollution (vehicular engine emission) exposure -induced exacerbation of atherosclerosis, associated with onset of clinical cardiovascular events.
Description:
Rationale: To determine vascular signaling pathways involved in air pollution (vehicular engine emission) exposure -induced exacerbation of atherosclerosis, associated with onset of clinical cardiovascular events. Objective: To elucidate the role of oxidized LDL (oxLDL) and its primary receptor on endothelial cells, the lectin-like oxLDL receptor (LOX-1), in regulation of endothelin-1 (ET-1) expression and matrix metalloproteinase (MMP) activity associated with inhalational exposure to vehicular engine emissions. Methods and Results: ApoE-1-mice were exposed by inhalation to filtered air or mixed engine exhaust (ME, 250ug PM/m3 diesel + 50ug PM/m3 gasoline exhausts) 6 h/d for 7 and 50 days. To test the hypothesis that LOX-1 is mediating the vascular. signaling responses to vehicular emission-exposure, mice were co-treated with either mouse IgG (control) or neutralizing antibodies to LOX-1 every other day throughout the 7-day ME exposure. ME-exposure increased oxLDL, vascular monocyte infiltration, and lipid peroxides, as well as LOX-1, MMP-9, and ET-1 mRNA expression. All indicators of ME-induced vascular inflammation and oxidative stress were attenuated by LOX-1 Ab treatment. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma soluble LOX-1 (sLOX). Conclusions: These findings demonstrate that acute exposure to vehicular source pollutants results in upregulation of vascular factors associated with progression of atherosclerosis, lipid peroxides, ET-1 and MMP-9, mediated through LOX-1 receptor signaling, which may serve as a novel target for future therapy. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
