title: Vehicular emissions induce vascular MMP-9 expression and activity associated with endothelin-1-mediated pathways.
abstract: 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.
  
  
  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 (approximately 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.
authors.affiliation: Lovelace Respiratory Research Institute,Department of Toxicology, Albuquerque, NM 87108, USA.
authors.forename: Amie K
authors.initials: AK
authors.lastname: Lund
authors.forename: JoAnn
authors.initials: J
authors.lastname: Lucero
authors.forename: Selitá
authors.initials: S
authors.lastname: Lucas
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: Travis L
authors.initials: TL
authors.lastname: Knuckles
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campen
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D015918:Infusion Pumps, Implantable; D019570:Inhalation Exposure; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000378:metabolism; D013113:Spin Labels; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D015854:Up-Regulation; D001335:Vehicle Emissions / Q000633:toxicity*; D055815:Young Adult
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D003497:Cyclic N-Oxides; D019332:Endothelin-1; D009566:Nitrates; D009573:Nitrites; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044022:Receptor, Endothelin A; D013113:Spin Labels; D001335:Vehicle Emissions; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C001803:tempol