MEK5 is activated by shear stress, activates ERK5 and induces KLF4 to modulate TNF responses in human dermal microvascular endothelial cells.
MEK5 is activated by shear stress, activates ERK5 and induces KLF4 to modulate TNF responses in human dermal microvascular endothelial cells.
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DOI：
10.1111/j.1549-8719.2010.00071.x
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发表时间：
2011-02
期刊：
影响因子：
--
通讯作者：
Pober JS
中科院分区：
文献类型：
--
作者：
Clark PR;Jensen TJ;Kluger MS;Morelock M;Hanidu A;Qi Z;Tatake RJ;Pober JS
内皮细胞（EC）内衬动脉响应层流剪切应力（LSS）通过抑制促炎性变化，部分通过激活MEK 5，ERK 5和诱导KLF 4。我们研究了这种抗炎途径是否在人类内皮细胞内衬微血管中起作用，微血管是炎症反应的主要部位。我们使用免疫荧光显微镜的人皮肤原位评估ERK 5激活和KLF 4在人真皮微血管（HDM）内皮细胞的表达。我们在培养的HDMECs中应用LSS或过表达组成型活性MEK 5（MEK 5/CA），并通过微阵列和qRT-PCR评估基因表达，通过蛋白质印迹评估蛋白质表达。我们使用qRT-PCR、FACS和HDMEC单层电阻的测量来评估MEK 5/CA对TNF应答的影响。我们使用siRNA敲低来评估ERK 5和KLF 4在这些反应中的作用。ERK 5磷酸化和KLF 4表达在HDMECs中原位观察到。在培养的HDMECs中，LSS激活ERK 5并诱导KLF 4。MEK 5/CA转导的HDMEC显示出活化的ERK 5和增加的KLF 4、血栓调节蛋白、eNOS和ICAM-1表达。MEK 5对KLF 4的诱导作用由ERK 5介导。MEK 5/CA转导的HDMEC对TNF的反应较低，这一作用部分由KLF 4介导。LSS激活MEK 5抑制微血管内皮细胞的炎症反应，部分是通过ERK 5依赖性诱导KLF 4。
Endothelial cells (ECs) lining arteries respond to laminar shear stress (LSS) by suppressing pro-inflammatory changes, in part through the activation of MEK5, ERK5 and induction of KLF4. We examined if this anti-inflammatory pathway operates in human ECs lining microvessels, the principal site of inflammatory responses. We used immunofluorescence microscopy of human skin to assess ERK5 activation and KLF4 expression in human dermal microvascular (HDM)ECs in situ. We applied LSS to or overexpressed constitutively active MEK5 (MEK5/CA) in cultured HDMECs and assessed gene expression by microarrays and qRT-PCR and protein expression by western blotting. We assessed effects of MEK5/CA on TNF responses using qRT-PCR, FACS and measurements of HDMEC monolayer electrical resistance. We used siRNA knockdown to assess the role of ERK5 and KLF4 in these responses. ERK5 phosphorylation and KLF4 expression is observed in HDMECs in situ. LSS activates ERK5 and induces KLF4 in cultured HDMECs. MEK5/CA-transduced HDMECs show activated ERK5 and increased KLF4, thrombomodulin, eNOS, and ICAM-1 expression. MEK5 induction of KLF4 is mediated by ERK5. MEK5/CA-transduced HDMECs are less responsive to TNF, an effect partly mediated by KLF4. MEK5 activation by LSS inhibits inflammatory responses in microvascular ECs, in part through ERK5-dependent induction of KLF4.
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影响因子：
4.4
作者：
Nagaoka, T;Yoshida, A
通讯作者：
Yoshida, A
影响因子：
6.5
作者：
Clark, Paul R.;Manes, Thomas D.;Kluger, Martin S.
通讯作者：
Kluger, Martin S.
影响因子：
20.3
作者：
Dekker, RJ;van Soest, S;Horrevoets, AJG
通讯作者：
Horrevoets, AJG
影响因子：
20.3
作者：
Fledderus, Joost O.;van Thienen, Johannes V.;Horrevoets, Anton J. G.
通讯作者：
Horrevoets, Anton J. G.
DOI：
10.1161/01.atv.0000215638.53414.99
发表时间：
2006-05-01
影响因子：
8.7
作者：
Lin, ZY;Hamik, A;Jain, MK
通讯作者：
Jain, MK