Yang Yanqiang, Parsons Kelly K, Chi Liqun, Malakauskas Sandra M, Le Thu H
University of Virginia, Box 800133, Charlottesville, VA 22908, USA.
Hypertension. 2009 Dec;54(6):1360-8. doi: 10.1161/HYPERTENSIONAHA.109.139428. Epub 2009 Oct 12.
Glutathione S-transferase-micro1, GSTM1, belongs to a superfamily of glutathione S-transferases that metabolizes a broad range of reactive oxygen species 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 with 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 reactive oxygen species and exhibit exaggerated p38 mitogen-activated protein kinase phosphorylation after exposure to H(2)O(2). To establish causality, we show that knockdown of Gstm1 by small interfering RNA results in increased proliferation of VSMCs in a dose-dependent manner, as well as in increased reactive oxygen species levels and VSMC migration. Moreover, Gstm1 small interfering RNA causes increased p38 mitogen-activated protein kinase phosphorylation and attenuates the antiproliferative effect of Tempol. Our data suggest that Gstm1 is a novel regulator of VSMC proliferation and migration through its role in handling reactive oxygen species. 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.
谷胱甘肽S-转移酶-微1（GSTM1）属于谷胱甘肽S-转移酶超家族，该家族可代谢多种活性氧和外源性物质。在不同物种中，导致Gstm1基因表达降低的遗传变异与血管疾病易感性增加有关，包括人类的动脉粥样硬化。我们之前在针对以肾血管中膜肥厚和增生为特征的肾血管损伤易感性的基因定位研究中，将Gstm1确定为一个定位候选基因。为了确定Gstm1在血管平滑肌细胞（VSMC）中的作用，我们从小鼠主动脉中分离出VSMC。我们证明，与抗性的129小鼠相比，易感的C57BL/6小鼠的VSMC中Gstm1 mRNA及其蛋白产物的表达降低。血清刺激后，C57BL/6 VSMC的增殖和迁移速度比129 VSMC快得多。此外，C57BL/6 VSMC具有更高水平的活性氧，并且在暴露于H2O2后表现出p38丝裂原活化蛋白激酶磷酸化增强。为了确定因果关系，我们表明，通过小干扰RNA敲低Gstm1会导致VSMC增殖呈剂量依赖性增加，以及活性氧水平升高和VSMC迁移增加。此外，Gstm1小干扰RNA会导致p38丝裂原活化蛋白激酶磷酸化增加，并减弱Tempol的抗增殖作用。我们的数据表明，Gstm1通过其在处理活性氧中的作用，是VSMC增殖和迁移的新型调节因子。导致Gstm1表达递减变化的遗传变异可能会导致氧化应激加剧的环境，从而导致对血管重塑和动脉粥样硬化的易感性。
