Glutathione S-transferase-micro1 regulates vascular smooth muscle cell proliferation, migration, and oxidative stress.
Glutathione S-transferase-micro1 regulates vascular smooth muscle cell proliferation, migration, and oxidative stress.
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DOI：
10.1161/hypertensionaha.109.139428
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Le TH
中科院分区：
文献类型：
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作者：
Yang Y;Parsons KK;Chi L;Malakauskas SM;Le TH
谷胱甘肽S转移酶μ-1，GSTM1，属于谷胱甘肽-S-转移酶超家族，可代谢多种活性氧(ROS)和外源物质。在不同物种中，导致GSTM1基因表达降低的基因变异与血管疾病的易感性增加有关，包括人类的动脉粥样硬化。我们先前在我们的基因定位研究中确定GSTM1是肾血管损伤易感性的候选基因，其特征是肾血管中层肥大和增生。为了确定GSTM1在血管平滑肌细胞(VSMCs)中的作用，我们从小鼠的主动脉中分离VSMCs。我们证明，与耐药的129只小鼠相比，易感的C57BL/6小鼠的VSMCs的GSTM1mRNA及其蛋白产物的表达减少。经血清刺激后，C57BL/6 VSMCs的增殖和迁移速度明显快于129 VSMCs。此外，C57BL/6 VSMCs在暴露于H_2O_2后具有更高的ROS水平，并表现出过度的p38 MAPK磷酸化。为了建立因果关系，我们证明了siRNA敲除GSTM1导致VSMCs以剂量依赖的方式增加增殖，以及增加ROS水平和VSM细胞迁移。此外，GSTM1 siRNA使p38MAPK的磷酸化增加，并减弱了temol的抗增殖作用。我们的数据表明，GSTM1是一种新的VSMC增殖和迁移的调节因子，它通过处理ROS的作用而发挥作用。引起GSTM1表达减量变化的基因变异可能允许过度氧化应激的环境，导致血管重构和动脉粥样硬化的易感性。
Glutathione S-transferase μ-1, GSTM1, belongs to a superfamily of glutathione-S-transferases that metabolize a broad range of reactive oxygen species (ROS) and xenobiotics. Across species, genetic variants that result in decreased expression of the Gstm1 gene are associated with increased susceptibility for vascular diseases, including atherosclerosis in humans. We previously identified Gstm1 as a positional candidate in our gene mapping study for susceptibility to renal vascular injury characterized by medial hypertrophy and hyperplasia of the renal vessels. To determine the role of Gstm1 in vascular smooth muscle cells (VSMCs), we isolated VSMCs from mouse aortas. We demonstrate that VSMCs from the susceptible C57BL/6 mice have reduced expression of Gstm1 mRNA and its protein product compared to that of the resistant 129 mice. After serum stimulation, C57BL/6 VSMCs proliferate and migrate at a much faster rate than 129 VSMCs. Furthermore, C57BL/6 VSMCs have higher levels of ROS, and exhibit exaggerated p38 MAPK phosphorylation after exposure to H2O2. To establish causality, we show that knockdown of Gstm1 by siRNA results in increased proliferation of VSMCs in a dose dependent manner, as well as in increased ROS levels and VSM cell migration. Moreover, Gstm1 siRNA causes increased p38 MAPK phosphorylation, and attenuates the anti-proliferative effect of TEMPOL. Our data suggest that Gstm1 is a novel regulator of VSMC proliferation and migration through its role in handling ROS. Genetic variants that cause a decremental change in expression of Gstm1 may permit an environment of exaggerated oxidative stress, leading to susceptibility to vascular remodeling and atherosclerosis.