Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling.
Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling.
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DOI：
10.1161/atvbaha.115.305857
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Grumbach IM
中科院分区：
文献类型：
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作者：
Klutho PJ;Pennington SM;Scott JA;Wilson KM;Gu SX;Doddapattar P;Xie L;Venema AN;Zhu LJ;Chauhan AK;Lentz SR;Grumbach IM
新出现的证据表明，蛋氨酸氧化可直接影响蛋白质功能，并可能与心血管疾病有关。本研究的目的是确定蛋氨酸亚砜还原酶A（MsrA）在血管疾病模型中的作用，并确定其信号通路。MsrA在人和鼠动脉血管壁的所有层中容易被识别。MsrA基因的缺失不影响载脂蛋白E缺陷小鼠动脉粥样硬化病变面积，对光化学损伤后实验性血栓形成的易感性也没有显著影响。相反，由于颈总动脉完全结扎导致血管损伤后的新生内膜面积在MsrA缺陷小鼠中显著大于对照小鼠。在主动脉血管平滑肌细胞（VSMC）缺乏MsrA，细胞增殖显着增加，由于加速G1/S转换。与此同时，细胞周期蛋白D1蛋白和cdk 4/细胞周期蛋白D1复合物的形成和活性增加，导致增强Rb磷酸化和E2 F的转录。最后，MsrA缺陷的VSMC表现出更大的ERK 1/2的激活，这是由Ras/Raf/MEK信号通路的活性增加引起的。我们的研究结果表明，MsrA作为一个负调节VSMC增殖和新生内膜增生血管损伤后通过控制Ras/Raf/MEK/ERK 1/2信号通路。
Emerging evidence suggests that methionine oxidation can directly affect protein function and may be linked to cardiovascular disease. The objective of this study was to define the role of the methionine sulfoxide reductase A (MsrA) in models of vascular disease and identify its signaling pathways. MsrA was readily identified in all layers of the vascular wall in human and murine arteries. Deletion of the MsrA gene did not affect atherosclerotic lesion area in apolipoprotein E-deficient mice, and had no significant effect on susceptibility to experimental thrombosis after photochemical injury. In contrast, the neointimal area after vascular injury due to complete ligation of the common carotid artery was significantly greater in MsrA-deficient compared to control mice. In aortic vascular smooth muscle cells (VSMC) lacking MsrA, cell proliferation was significantly increased due to accelerated G1/S transition. In parallel, cyclin D1 protein and cdk4/cyclin D1 complex formation and activity were increased in MsrA-deficient VSMC, leading to enhanced Rb phosphorylation and transcription of E2F. Finally, MsrA-deficient VSMC exhibited greater activation of ERK1/2 that was caused by increased activity of the Ras/Raf/MEK signaling pathway. Our findings implicate MsrA as a negative regulator of VSMC proliferation and neointimal hyperplasia after vascular injury through control of the Ras/Raf/MEK/ERK1/2 signaling pathway.