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), following 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 h/d for 1 or 7 days. Concurrently, mice were treated with either ETA receptor antagonist BQ-123 (100 ng/kg/day) via osmotic minipumps, Tempol (∼41 mg/kg/day, 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 - ETA receptor pathways.

Ultrastructural changes in atherosclerotic plaques following the instillation of airborne particulate matter into the lungs of rabbits

“…Sun et al (27,28) used an apolipoprotein E knockout (ApoE -/-) mouse model to show that long-term exposure to low concentrations of PM 2.5 (particles smaller than 2.5 µm in diameter) altered vasomotor tone, and increased tissue-factor expression, vascular inflammation and atherosclerotic burden in these animals. Research at the Lovelace Respiratory Research Institute (New Mexico, USA) in ApoE -/-mice has shown vascular remodelling and altered atherosclerotic plaque composition following PM 10 exposure and diesel emission exposure (29)(30)(31). The present study was designed to determine whether and how PM 10 exposure affected the architecture of existing atherosclerotic plaques and to determine whether the observed ultrastructure was consistent with the characteristics of a more vulnerable atherosclerotic plaque.…”

“…Several studies in the ApoE -/-mouse have shown the transcriptional upregulation of factors associated with vascular remodelling including MMP-3, -7 and -9 following PM 10 exposure (29,30), and MMP-9 following diesel exhaust exposure (31). Future work testing for colocalization of these MMPs with migrating foam cells in the WHHL rabbit model would be of interest.…”

Particulate Matter Air Pollution and Cardiovascular Disease

“…There may also exist some synergy between vapor phase, gas, and particle constituents in relation to instigation of cardiovascular responses. Recently, 364 it was demonstrated in apoE Ϫ/Ϫ mice that whole gasoline engine exhaust over 1 or 7 days increased vascular messenger ribonucleic acid expression of matrix metalloproteinase (MMP)-2 and MMP-9. Levels of ET-1 and ROS were similarly increased.…”

Interaction of matrix metalloproteinases with pulmonary pollutants: Table 1–

“…In order to investigate the mechanisms of cardiovascular disease exacerbations induced by traffic-related pollutants, LUND et al [86] examined modulation of vascular MMP-2 and -9 expression and activity by gasoline engine exhaust in a wellcharacterised model of vascular toxicity, the apolipoprotein E knockout (ApoE -/-) mouse. Animals were exposed to gasoline engine exhaust (60 mg?m -3 particulate matter whole exhaust) or filtered air for 6 h?day -1 for a period of 1 or 7 days.…”

“…1) MMP-2 and -9 can be induced via TLR4 (nickel exposure) [92] or secondary to oxidative signalling (gasoline exposure) [86]. In addition, MMP-9 can be induced via fra-1, a heterodimeric partner of AP-1, which binds to and activates the MMP-9 promoter (DEP exposure).…”