Department of Biomedical Engineering, College of Engineering, Chung Yuan Christian University, Zhongli District, Taoyuan City, 32023, Taiwan.
Center for Nanotechnology, Chung Yuan Christian University, Zhongli District, Taoyuan City, 32023, Taiwan.
Cardiovasc Toxicol. 2017 Oct;17(4):384-392. doi: 10.1007/s12012-016-9364-0.
Epidemiological studies suggest that an increase of diesel exhaust particles (DEP) in ambient air corresponds to an increase in hospital-recorded myocardial infarctions within 48 h after exposure. Among the many theories to explain this data are endothelial dysfunction and translocation of DEP into vasculature. The mechanisms for such DEP-induced vascular permeability remain unknown. One of the major mechanisms underlying the effects of DEP is suggested to be oxidative stress. Experiments have shown that DEP induce the generation of reactive oxygen species (ROS), such as superoxide anion and HO in the HUVEC tube cells. Transcription factor Nrf2 is translocated to the cell nucleus, where it activates transcription of the antioxidative enzyme HO-1 and sequentially induces the release of vascular permeability factor VEGF-A. Furthermore, a recent study shows that DEP-induced intracellular ROS may cause the release of pro-inflammatory TNF-α and IL-6, which may induce endothelial permeability as well by promoting VEGF-A secretion independently of HO-1 activation. These results demonstrated that the adherens junction molecule, VE-cadherin, becomes redistributed from the membrane at cell-cell borders to the cytoplasm in response to DEP, separating the plasma membranes of adjacent cells. DEP were occasionally found in endothelial cell cytoplasm and in tube lumen. In addition, the induced ROS is cytotoxic to the endothelial tube-like HUVEC. Acute DEP exposure stimulates ATP depletion, followed by depolarization of their actin cytoskeleton, which sequentially inhibits PI3K/Akt activity and induces endothelial apoptosis. Nevertheless, high-dose DEP augments tube cell apoptosis up to 70 % but disrupts the p53 negative regulator Mdm2. In summary, exposure to DEP affects parameters influencing vasculature permeability and viability, i.e., oxidative stress and its upregulated antioxidative and pro-inflammatory responses, which sequentially induce vascular permeability factor, VEGF-A release and disrupt cell-cell junction integrity. While exposure to a low dose of DEP actin triggers cytoskeleton depolarization, reduces PI3K/Akt activity, and induces a p53/Mdm2 feedback loop, a high dose causes apoptosis by depleting Mdm2. Addition of ROS scavenger N-acetyl cysteine suppresses DEP-induced oxidative stress efficiently and reduces subsequent damages by increasing endogenous glutathione.
流行病学研究表明，环境空气中柴油废气颗粒 (DEP) 的增加与暴露后 48 小时内医院记录的心肌梗死增加相对应。有许多理论可以解释这一数据，其中包括内皮功能障碍和 DEP 向血管内易位。DEP 引起的这种血管通透性增加的机制尚不清楚。DEP 影响的主要机制之一被认为是氧化应激。实验表明，DEP 会诱导活性氧 (ROS) 的产生，如超氧阴离子和 HUVEC 管腔细胞中的 HO。转录因子 Nrf2 易位到细胞核，在那里它激活抗氧化酶 HO-1 的转录，并顺序诱导血管通透性因子 VEGF-A 的释放。此外，最近的一项研究表明，DEP 诱导的细胞内 ROS 可能导致促炎 TNF-α和 IL-6 的释放，这也可能通过独立于 HO-1 激活促进 VEGF-A 分泌来诱导内皮通透性。这些结果表明，粘附连接分子 VE-钙粘蛋白从细胞-细胞边界的膜重新分布到细胞质中，以响应 DEP，使相邻细胞的质膜分离。DEP 偶尔在血管内皮细胞细胞质和管腔中被发现。此外，诱导的 ROS 对内皮管状 HUVEC 具有细胞毒性。急性 DEP 暴露刺激 ATP 耗竭，随后其肌动蛋白细胞骨架去极化，从而依次抑制 PI3K/Akt 活性并诱导内皮细胞凋亡。然而，高剂量 DEP 增加高达 70%的管腔细胞凋亡，但破坏 p53 负调节剂 Mdm2。总之，暴露于 DEP 会影响影响血管通透性和活力的参数，即氧化应激及其上调的抗氧化和促炎反应，这会顺序诱导血管通透性因子、VEGF-A 的释放，并破坏细胞-细胞连接的完整性。虽然低剂量 DEP 的暴露会触发细胞骨架去极化，降低 PI3K/Akt 活性，并诱导 p53/Mdm2 反馈回路，但高剂量 DEP 会通过耗尽 Mdm2 导致细胞凋亡。添加 ROS 清除剂 N-乙酰半胱氨酸可通过增加内源性谷胱甘肽有效地抑制 DEP 诱导的氧化应激，并减少随后的损伤。
