Cyclic strain stress-induced mitogen-activated protein kinase (MAPK) phosphatase 1 expression in vascular smooth muscle cells is regulated by Ras/Rac-MAPK pathways
Cyclic strain stress-induced mitogen-activated protein kinase (MAPK) phosphatase 1 expression in vascular smooth muscle cells is regulated by Ras/Rac-MAPK pathways
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DOI：
10.1074/jbc.274.36.25273
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发表时间：
1999-09-03
影响因子：
4.8
通讯作者：
Xu, QB
中科院分区：
文献类型：
--
作者：
Li, CH;Hu, YH;Xu, QB
最近，我们发现机械应激导致血管平滑肌细胞(VSMCs)中血小板衍生生长因子受体的快速磷酸化或激活，继而激活丝裂原激活蛋白激酶(MAPKs)和AP-1转录因子(Hu，Y，，Beck，G，，Wick，G.和Xu，Q，(1998)FASE B J.12,1135-1142)。在这里，我们提供的证据表明，VSMC对机械应力的反应还包括诱导MAPK磷酸酶-1(MKP-1)，这可能是MAPK信号通路的负调节因子。当培养在柔性膜上的大鼠VSMCs受到循环应变应力(60个循环/分钟，5-30%伸长率)时，MKP-1蛋白和mRNA的诱导具有时间和强度依赖性。同时，机械力可引起细胞外信号调节蛋白激酶(ERKs)、c-jun氨基末端蛋白激酶(JNKs)或应激激活蛋白激酶(SAPKs)和p38MAPKs等MAPKs的快速和瞬时激活。生长因子受体拮抗剂苏拉明可完全阻断ERK的激活，显著阻断机械应激时MKP-1的表达，但不能阻断JNK/SAPKs和p38MAPK的激活。有趣的是，稳定表达显性负性RAS(RAS N17)或RAC(RACN17)的VSMC株MKP-1表达显著降低，PD 98059抑制ERK激酶(MEK1/2)或SE 202190抑制p38MAPKs导致MKP-1诱导下调。此外，在VSMCs中过表达MKP-1导致ERKs、JNKs/SAPKs和p38MAPKs的去磷酸化和失活，并抑制DNA合成。综上所述，我们的结果表明，机械应激诱导MKP-1的表达受生长因子受体-RAS-ERK和RAC-JNK/SAPK或p38MAPK两条信号通路的调控，MKP-1通过MAPK失活来抑制VSMC的增殖。这些结果表明，MKP-1在机械应激刺激的VSMC生长和分化信号中起关键作用。
Recently, we demonstrated that mechanical stress results in rapid phosphorylation or activation of platelet-derived growth factor receptors in vascular smooth muscle cells (VSMCs) followed by activation of mitogen-activated protein kinases (MAPKs) and AP-1 transcription factors (Hu, Y,, Beck, G,, Wick, G., and Xu, Q, (1998) FASEB J. 12, 1135-1142). Herein, we provide evidence that VSMC responses to mechanical stress also include induction of MAPK phosphatase-1 (MKP-1), which may serve as a negative regulator of MAPK signaling pathways. When rat VSMCs cultivated on a flexible membrane were subjected to cyclic strain stress (60 cycles/ min, 5-30% elongation), induction of MKP-1 proteins and mRNA was observed in time- and strength-dependent manners. Concomitantly, mechanical forces evoked rapid and transient activation of all three members of MAPKs, i.e. extracellular signal-regulated kinases (ERKs), c-Jun NH2-terminal protein kinases (JNKs), or stress-activated protein kinases (SAPKs), and p38 MAPKs. Suramin, a growth factor receptor antagonist, completely abolished ERK activation, significantly blocked MKP-1 expression, but not JNK/SAPKs and p38 MAPK activation, in response to mechanical stress. Interestingly, VSMC lines stably expressing dominant negative Ras (Ras N17) or Rac (Rac N17) exhibited a marked decrease in MKP-1 expression; the inhibition of ERK kinases (MEK1/2) by PD 98059 or of p38 MAPKs by SE 202190 resulted in a down-regulation of MKP-1 induction. Furthermore, overexpressing MKP-1 in VSMCs led to the dephosphorylation and inactivation of ERKs, JNKs/SAPKs, and p38 MAPKs and inhibition of DNA synthesis. Taken together, our findings demonstrate that mechanical stress induces MKP-1 expression regulated by two signal pathways, including growth factor receptor-Ras-ERK and Rac-JNK/SAPK or p38 MAPK, and that MKP-1 inhibits VSMC proliferation via MAPK inactivation. These results suggest that MKP-1 plays a crucial role in mechanical stress-stimulated signaling leading to VSMC growth and differentiation.