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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Regulation of vascular smooth muscle migration by mitogen-activated protein kinase and calcium/calmodulin-dependent protein kinase II signaling pathways.
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Regulation of vascular smooth muscle migration by mitogen-activated protein kinase and calcium/calmodulin-dependent protein kinase II signaling pathways.

机译：有丝分裂原激活的蛋白激酶和钙/钙调蛋白依赖性蛋白激酶II信号通路对血管平滑肌迁移的调节。

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摘要

Platelet-derived growth factor BB (PDGF BB) activation of the mitogen-activated protein kinases (MAPK), ERK1 and ERK2, has been shown to be necessary for mitogen-stimulated proliferation, but its role in regulating cell migration and its relationship to other chemotactic signaling events, such as CamKII activation, has not been defined. Using a modified Boyden chamber apparatus, we tested the effects of a selective inhibitor of the upstream activator of ERK1/2, MEK1, on PDGF-stimulated rat aortic vascular smooth muscle cells (VSMCs) alone and in combination with KN62, a selective inhibitor of CamKII. The MEK1 inhibitor, PD98059, caused a dose-dependent reduction in ERK2 activity that paralleled a decrease in migration up to 60%. This inhibition of migration was similar to that seen with KN62 and the combined effects of both inhibitors were non-additive. Although KN62 did not affect ERK2 activity in response to PDGF, PD98059 markedly inhibited PDGF-stimulated CamKII activity, suggesting that activation of CamKII by PDGF was dependent on ERK activity and that the effects of ERK inhibition on migration may be mediated through its ability to inhibit CamKII activity. To directly test this, VSMCs were infected with a recombinant adenovirus expressing constitutively activated CamKII. Infection reversed the inhibitory effects of KN62 on migration, but had no effect on the inhibition of migration seen with PD98059. These results suggest that while MAPK may act upstream of CamKII to control its activation in response to PDGF, it also regulates migration independently of CamKII activation.
机译：血小板源性生长因子BB（PDGF BB）对促分裂原活化蛋白激酶（MAPK），ERK1和ERK2的激活已显示是促分裂原刺激的增殖所必需的，但其在调节细胞迁移中的作用及其与其他物质的关系趋化信号事件，如CamKII激活，尚未定义。我们使用改良的Boyden腔室设备，测试了ERK1 / 2上游激活剂选择性抑制剂MEK1对PDGF刺激的大鼠主动脉血管平滑肌细胞（VSMC）的单独作用以及与KN62联合的选择性抑制剂CamKII。 MEK1抑制剂PD98059导致ERK2活性呈剂量依赖性降低，与迁移降低60％平行。这种对迁移的抑制作用与KN62相似，并且两种抑制剂的联合作用均为非累加作用。尽管KN62不会影响对PDGF的ERK2活性，但PD98059显着抑制了PDGF刺激的CamKII活性，这表明PDGF对CamKII的激活取决于ERK活性，并且ERK抑制迁移的作用可能是通过其抑制能力来介导的。 CamKII活动。为了直接对此进行测试，VSMC用表达组成型激活的CamKII的重组腺病毒感染。感染逆转了KN62对迁移的抑制作用，但对PD98059所见的迁移抑制没有影响。这些结果表明，虽然MAPK可能在CamKII的上游起作用，以响应PDGF来控制其激活，但它也独立于CamKII激活来调节迁移。

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