Big mitogen-activated protein kinase 1 protects cultured rat aortic smooth muscle cells from oxidative damage.
Big mitogen-activated protein kinase 1 protects cultured rat aortic smooth muscle cells from oxidative damage.
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DOI：
10.1254/jphs.11015fp
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发表时间：
2011
影响因子：
3.5
通讯作者：
Jing Zhao-;Yoji Kyotani;S. Itoh;H. Nakayama;M. Isosaki;M. Yoshizumi
中科院分区：
文献类型：
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作者：
Jing Zhao-;Yoji Kyotani;S. Itoh;H. Nakayama;M. Isosaki;M. Yoshizumi
氧化应激被认为是动脉硬化的主要介质。在血管平滑肌细胞中，氧化应激诱导的细胞死亡（包括细胞凋亡）可能与动脉硬化中的动脉钙化有关。大丝裂原激活蛋白激酶-1 / 细胞外信号调节激酶 5 (BMK1/ERK5) 是丝裂原激活蛋白激酶家族中新发现的成员。与 Src 酪氨酸激酶一样，BMK1/ERK5 已知对氧化应激敏感；然而，人们对其病理生理学意义知之甚少。在这项研究中，我们使用培养的大鼠主动脉平滑肌细胞（RASMC）研究了 BMK1 和 Src 在 H(2)O(2) 诱导的细胞死亡中的作用。采用 TdT 介导的 dUTP 缺口末端标记 (TUNEL) 方法评估细胞凋亡，并通过 Western blotting 测定 BMK1 和 Src 活性。主要结果如下： 1）H(2)O(2)在RASMCs中以时间和浓度依赖性方式激活BMK1和Src； 2) 在 Src 敲低 RASMC 和用 Src 家族激酶抑制剂 4-氨基-5-(4-氯苯基)-7-(叔丁基)吡唑并[3,4-d]嘧啶 (PP2) 预处理的 RASMC 中，H(2)O(2) 激活的 BMK1 均减弱； 3) BMK1 和 Src 敲低的 RASMC 以及 PP2 处理的 RASMC 中 H(2)O(2) 诱导的细胞死亡增加。这些发现表明，Src 和 BMK1 可能对 RASMC 中氧化应激诱导的死亡发挥防御和抵抗作用。
Oxidative stress is considered a major mediator of arteriosclerosis. In vascular smooth muscle cells, oxidative stress-induced cell death (including apoptosis) is probably related to arterial calcification in arteriosclerosis. Big mitogen-activated protein kinase-1 / extracellular signal-regulated kinase 5 (BMK1/ERK5) is a newly identified member of the mitogen-activated protein kinases family. Like Src tyrosine kinase, BMK1/ERK5 is known to be sensitive to oxidative stress; however, its pathophysiological significance is poorly understood. In this study, we investigated the involvement of BMK1 and Src in H(2)O(2)-induced cell death using cultured rat aortic smooth muscle cells (RASMCs). Cell apoptosis was evaluated by using the TdT-mediated dUTP nick end labeling (TUNEL) method, and BMK1 and Src activities were determined by Western blotting. The main results are as follows: 1) BMK1 and Src were activated by H(2)O(2) in a time- and concentration-dependent manner in RASMCs; 2) BMK1 activation by H(2)O(2) was attenuated both in Src-knockdown RASMCs and in RASMCs pretreated with 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a Src family kinases inhibitor; and 3) H(2)O(2)-induced cell death was increased in BMK1- and Src-knockdown RASMCs as well as in PP2-treated RASMCs. These findings suggested that Src and BMK1 may play defensive and resistive roles against oxidative stress-induced death in RASMCs.