Department of Biochemistry and Molecular Biology, Chosun University School of Medicine, Gwangju, 61452, Korea.
Cancer Mutation Research Center, Chosun University, Gwangju, 61452, Korea.
Part Fibre Toxicol. 2022 Apr 22;19(1):29. doi: 10.1186/s12989-022-00472-z.
Epidemiological studies have suggested that elevated concentrations of particulate matter (PM) are strongly associated with the incidence of atherosclerosis, however, the underlying cellular and molecular mechanisms of atherosclerosis by PM exposure and the components that are mainly responsible for this adverse effect remain to be established. In this investigation, we evaluated the effects of ambient PM on vascular smooth muscle cell (VSMC) behavior. Furthermore, the effects of polycyclic aromatic hydrocarbons (PAHs), major components of PM, on VSMC migration and the underlying mechanisms were examined.
VSMC migration was significantly increased by treatment with organic matters extracted from ambient PM. The total amount of PAHs contained in WPM was higher than that in SPM, leading to higher ROS generation and VSMC migration. The increased migration was successfully inhibited by treatment with the anti-oxidant, N-acetyl-cysteine (NAC). The levels of matrix metalloproteinase (MMP) 2 and 9 were significantly increased in ambient PM-treated VSMCs, with MMP9 levels being significantly higher in WPM-treated VSMCs than in those treated with SPM. As expected, migration was significantly increased in all tested PAHs (anthracene, ANT; benz(a)anthracene, BaA) and their oxygenated derivatives (9,10-Anthraquinone, AQ; 7,12-benz(a)anthraquinone, BAQ, respectively). The phosphorylated levels of focal adhesion kinase (FAK) and formation of the focal adhesion complex were significantly increased in ambient PM or PAH-treated VSMCs, and these effects were blocked by administration of NAC or α-NF, an inhibitor of AhR, the receptor that allows PAH uptake. Subsequently, the levels of phosphorylated Src and NRF, the downstream targets of FAK, were altered with a pattern similar to that of p-FAK.
PAHs, including oxy-PAHs, in ambient PM may have dual effects that lead to an increase in VSMC migration. One is the generation of oxidative stress followed by MMP upregulation, and the other is actin reorganization that results from the activation of the focal adhesion complex.
流行病学研究表明，颗粒物（PM）浓度升高与动脉粥样硬化的发生密切相关，然而，PM 暴露导致动脉粥样硬化的潜在细胞和分子机制以及主要负责这种不良效应的成分仍有待确定。在这项研究中，我们评估了环境 PM 对血管平滑肌细胞（VSMC）行为的影响。此外，还研究了多环芳烃（PAHs）作为 PM 的主要成分对 VSMC 迁移的影响及其潜在机制。
有机提取物处理后，VSMC 迁移明显增加。WPM 中总 PAHs 含量高于 SPM，导致 ROS 生成和 VSMC 迁移增加。抗氧化剂 N-乙酰半胱氨酸（NAC）处理可成功抑制迁移增加。环境 PM 处理的 VSMC 中基质金属蛋白酶（MMP）2 和 9 的水平明显升高，WPM 处理的 VSMC 中 MMP9 水平明显高于 SPM 处理的 VSMC。正如预期的那样，所有测试的 PAHs（蒽、ANT；苯并（a）蒽、BaA）及其氧化衍生物（9,10-蒽醌、AQ；7,12-苯并（a）蒽醌、BAQ）都显著增加了迁移。在环境 PM 或 PAH 处理的 VSMC 中，粘着斑激酶（FAK）的磷酸化水平和粘着斑复合物的形成显著增加，这些作用被 NAC 或 AhR 抑制剂α-NF 阻断，AhR 是允许 PAH 摄取的受体。随后，FAK 的下游靶点 Src 和 NRF 的磷酸化水平发生改变，与 p-FAK 的变化模式相似。
环境 PM 中的 PAHs，包括氧化 PAHs，可能具有双重作用，导致 VSMC 迁移增加。一种是氧化应激导致 MMP 上调，另一种是粘着斑复合物激活导致肌动蛋白重排。
