Ischemia/reperfusion-induced MKP-3 impairs endothelial NO formation via inactivation of ERK1/2 pathway.
Ischemia/reperfusion-induced MKP-3 impairs endothelial NO formation via inactivation of ERK1/2 pathway.
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缺血/再灌注诱导的 MKP-3 通过 ERK1/2 通路失活损害内皮 NO 形成
DOI：
10.1371/journal.pone.0042076
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Yang D;Xie P;Liu Z
丝裂原活化蛋白激酶磷酸酶（MKPs）是一个双特异性磷酸酶家族。内皮细胞表达多种MKP家族成员，如MKP-3。然而，MKP-3对内皮生物学过程的影响尚未完全阐明。在这里，我们解决缺血/再灌注（IS/RP）条件下MKP-3和内皮一氧化氮（NO）的形成之间的关联。对人脐静脉内皮细胞（HUVEC）进行IS/RP处理。检测MKP-3表达和NO生成。IS/RP诱导内皮细胞MKP-3表达，抑制eNOS表达和NO生成，并伴有内皮细胞凋亡增加。siRNA实验表明，MKP-3是一个重要的介质，在损害eNOS表达和NO的生产在内皮细胞。用组成型活性ERK质粒转染HUVECs，提示MKP-3的上述作用是通过灭活ERK 1/2通路实现的。此外，eNOS表达的损伤通过组蛋白去乙酰化酶（HDAC）抑制剂的治疗而恢复，并且与组蛋白去乙酰化和HDAC 1向eNOS启动子的募集有关。丹参素A（SalA）可明显减弱IS/RP条件下内皮细胞MKP-3的诱导和eNOS表达及NO生成的抑制作用。总的来说，这些结果首次表明，IS/RP抑制eNOS表达的ERK 1/2和招聘的HDAC 1基因启动子的失活，导致减少NO的形成，通过MKP-3依赖的机制在内皮细胞中，和SalA具有治疗意义，在保护内皮细胞受损的NO的形成响应IS/RP。
Mitogen-activated protein kinase phosphatases (MKPs) are a family of dual-specificity phosphatases. Endothelial cells express multiple MKP family members, such as MKP-3. However, the effects of MKP-3 on endothelial biological processes have not yet been fully elucidated. Here, we address the association between MKP-3 and endothelial Nitric oxide (NO) formation under ischemia/reperfusion (IS/RP) condition. Human umbilical vein endothelial cells (HUVECs) were subjected to IS/RP treatment. The MKP-3 expression and NO formation were examined. IS/RP induced endothelial MKP-3 expression and inhibited eNOS expression and NO formation, accompanied by an increase of endothelial apoptosis. The siRNA experiments showed that MKP-3 was an important mediator in impairing eNOS expression and NO production in endothelial cells. Transfection of HUVECs with constitutively active ERK plasmids suggested that the above mentioned effect of MKP-3 was via inactivation of ERK1/2 pathway. Furthermore, impairment of eNOS expression was restored by treatment of histone deacetylase (HDAC) inhibitor and related to histone deacetylation and recruitment of HDAC1 to the eNOS promoter. Finally, Salvianolic acid A (SalA) markedly attenuated induction of MKP-3 and inhibition of eNOS expression and NO formation under endothelial IS/RP condition. Overall, these results for the first time demonstrated that IS/RP inhibited eNOS expression by inactivation of ERK1/2 and recruitment of HDAC1 to the gene promoter, leading to decreased NO formation through a MKP-3-dependent mechanism in endothelial cells, and SalA has therapeutic significance in protecting endothelial cells from impaired NO formation in response to IS/RP.
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salvianolic酸：具有多种心血管保护机制的小型化合物。
影响因子：
11
作者：
Ho JH;Hong CY
通讯作者：
Hong CY
影响因子：
5.6
作者：
Oh, Kwang-Seok;Oh, Byung Koo;Lee, Byung Ho
通讯作者：
Lee, Byung Ho
影响因子：
4.5
作者：
Fleming, Ingrid
通讯作者：
Fleming, Ingrid
影响因子：
4.8
作者：
Bauer, PM;Fulton, D;Sessa, WC
通讯作者：
Sessa, WC
影响因子：
7.5
作者：
Furukawa, T;Fujisaki, R;Horii, A
通讯作者：
Horii, A