MMP-9-Dependent Serum-Borne Bioactivity Caused by Multiwalled Carbon Nanotube Exposure Induces Vascular Dysfunction via the CD36 Scavenger Receptor.
MMP-9-Dependent Serum-Borne Bioactivity Caused by Multiwalled Carbon Nanotube Exposure Induces Vascular Dysfunction via the CD36 Scavenger Receptor.
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由多壁碳纳米管暴露引起的MMP-9依赖性血清传播生物活性通过CD36清道夫受体诱导血管功能障碍。
DOI：
10.1093/toxsci/kfw015
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Campen MJ
中科院分区：
文献类型：
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作者：
Aragon M;Erdely A;Bishop L;Salmen R;Weaver J;Liu J;Hall P;Eye T;Kodali V;Zeidler-Erdely P;Stafflinger JE;Ottens AK;Campen MJ
吸入多壁碳纳米管（MWCNT）可引起全身性效应，包括血管炎症、内皮功能障碍和急性期蛋白表达。MWCNT仅最低限度地易位到肺之外，因此其心血管效应可能是由从MWCNT-肺相互作用溢出到体循环中的次级生物分子因子的产生引起的。因此，我们假设，诱导基质金属蛋白酶-9（MMP-9）是一个发电机的因素，反过来，驱动血管效应，通过配体-受体相互作用与多配体模式识别受体，CD 36。为了测试这一点，野生型（WT; C57 BL/6）和MMP-9−/−小鼠通过口咽抽吸暴露于不同剂量（10或40 μg）的MWCNT，并在暴露后4和24小时收集血清。内皮细胞处理血清从MWCNT暴露的WT小鼠表现出显着减少一氧化氮（NO）的产生，通过电子顺磁共振测量，效果是独立的NO清除。在两个时间点，来自MWCNT暴露的WT小鼠的血清抑制乙酰胆碱（ACh）介导的主动脉环舒张。主动脉环上缺乏CD 36（从CD 36缺陷小鼠获得）消除了血清诱导的血管舒张损伤。多壁碳纳米管暴露诱导MMP-9蛋白水平在支气管肺泡灌洗液和全肺裂解物。暴露于MWCNT的MMP-9−/−小鼠的血清未降低未处理WT主动脉环的血管舒张幅度，尽管相对于对照组，在两个MWCNT剂量组中观察到ACh剂量-反应曲线适度右移。总之，肺暴露于多壁碳纳米管导致MMP-9水平升高和MMP-9依赖性循环生物活性因子的产生，通过与血管CD 36的相互作用促进内皮功能障碍和降低NO生物利用度。
Inhalation of multi walled carbon nanotubes (MWCNT) causes systemic effects including vascular inflammation, endothelial dysfunction, and acute phase protein expression. MWCNTs translocate only minimally beyond the lungs, thus cardiovascular effects thereof may be caused by generation of secondary biomolecular factors from MWCNT-pulmonary interactions that spill over into the systemic circulation. Therefore, we hypothesized that induced matrix metalloproteinase-9 (MMP-9) is a generator of factors that, in turn, drive vascular effects through ligand-receptor interactions with the multiligand pattern recognition receptor, CD36. To test this, wildtype (WT; C57BL/6) and MMP-9−/− mice were exposed to varying doses (10 or 40 μg) of MWCNTs via oropharyngeal aspiration and serum was collected at 4 and 24 h postexposure. Endothelial cells treated with serum from MWCNT-exposed WT mice exhibited significantly reduced nitric oxide (NO) generation, as measured by electron paramagnetic resonance, an effect that was independent of NO scavenging. Serum from MWCNT-exposed WT mice inhibited acetylcholine (ACh)-mediated relaxation of aortic rings at both time points. Absence of CD36 on the aortic rings (obtained from CD36-deficient mice) abolished the serum-induced impairment of vasorelaxation. MWCNT exposure induced MMP-9 protein levels in both bronchoalveolar lavage and whole lung lysates. Serum from MMP-9−/− mice exposed to MWCNT did not diminish the magnitude of vasorelaxation in naïve WT aortic rings, although a modest right shift of the ACh dose-response curve was observed in both MWCNT dose groups relative to controls. In conclusion, pulmonary exposure to MWCNT leads to elevated MMP-9 levels and MMP-9-dependent generation of circulating bioactive factors that promote endothelial dysfunction and decreased NO bioavailability via interaction with vascular CD36.