Vehicular emissions induce vascular MMP-9 expression and activity associated with endothelin-1-mediated pathways.
Vehicular emissions induce vascular MMP-9 expression and activity associated with endothelin-1-mediated pathways.
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DOI：
10.1161/atvbaha.108.176107
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发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Campen MJ
中科院分区：
文献类型：
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作者：
Lund AK;Lucero J;Lucas S;Madden MC;McDonald JD;Seagrave JC;Knuckles TL;Campen MJ
空气污染导致心血管疾病恶化的机制目前尚不清楚，因此我们研究了血管内皮素-1 （ET-1）和活性氧（ROS）在暴露于汽车发动机排放后调节血管重构介质（即基质金属蛋白酶（MMPs））中的作用。将ApoE-/-小鼠吸入过滤空气或汽油机废气（GEE， 1:12稀释）6 h/d，持续1或7天。同时，小鼠通过渗透微型泵、Tempol （~ 41 mg/kg/天，口服）或载体分别给予ETA受体拮抗剂BQ-123 （100 ng/kg/天）。gee暴露增加血管MMP-2和-9、内皮素-1 （ET-1）、组织金属蛋白酶抑制剂(TIMP)-2 mRNA和ROS水平。主动脉MMP蛋白和血浆MMP-9同样上调。经tempol处理后，gee介导的血管ROS升高，以及MMP-2和TIMP-2减弱；而BQ-123则改善了gee诱导的血管中MMP-9、MMP-2、ROS和ET-1的表达。在一项平行研究中，志愿者暴露于柴油废气中，血浆ET-1和MMP-9的表达和活性显著增加。这些发现表明，急性暴露于车辆源空气污染物会导致与动脉粥样硬化进展相关的循环和血管因子的上调，部分是通过激活ET-1 - ETA受体途径介导的。
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. 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. 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.