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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:511.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Vehicular Emissions Induce Vascular MMP-9 Expression and Activity Associated With Endothelin-1–Mediated Pathways

Amie K. Lund; JoAnn Lucero; Selitá Lucas; Michael C. Madden; Jacob D. McDonald; Jean-Clare Seagrave; Travis L. Knuckles; Matthew J. Campen

From the Lovelace Respiratory Research Institute, Department of Toxicology (A.K.L., J.L., S.L., J.D.M., J.-C.S., T.L.K., M.J.C.), Albuquerque, NM; and the National Health and Environmental Effects Research Laboratory, Office of Research and Development (M.C.M.), U.S. Environmental Protection Agency, Chapel Hill, NC.

Correspondence to Matthew J. Campen, PhD, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr SE, Albuquerque, NM 87108. E-mail mcampen{at}lrri.org

Objective— Mechanisms of air pollution–induced exacerbation of cardiovascular disease are currently unknown, thus we examined the roles of vascular endothelin-1 (ET-1) and reactive oxygen species (ROS) in regulating mediators of vascular remodeling, namely matrix metalloproteinases (MMPs), after exposure to vehicle engine emissions.

Methods and Results— ApoE^–/– mice were exposed by inhalation to filtered air or gasoline engine exhaust (GEE, 1:12 dilution) 6 hours per day for 1 or 7 days. Concurrently, mice were treated with either ET_A receptor antagonist BQ-123 (100 ng/kg/d) via osmotic minipumps, Tempol (41 mg/kg/d, orally), or vehicle. GEE-exposure increased vascular MMP-2 and -9, endothelin-1 (ET-1), tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and ROS levels. Aortic MMP protein and plasma MMP-9 were similarly upregulated. GEE-mediated increases in vascular ROS were attenuated by Tempol-treatment, as were MMP-2 and TIMP-2; whereas BQ-123 ameliorated GEE-induced vascular expression of MMP-9, MMP-2, ROS, and ET-1. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma ET-1 and MMP-9 expression and activity.

Conclusions— These findings demonstrate that acute exposure to vehicular source air pollutants results in upregulation of circulating and vascular factors associated with progression of atherosclerosis, mediated in part through activation of ET-1–ET_A receptor pathways.

Key Words: atherosclerosis • endothelin-1 • matrix metalloproteinase • reactive oxygen species • air pollution

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