From the Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany and DZHK (German Centre for Cardiovascular Research) partner site Rhine-Main (N.Z., R.A.M., T.F., R.P., E.B., I.F., B.F.); and Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (B.S., N.W.).
Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2792-9. doi: 10.1161/ATVBAHA.113.301848. Epub 2013 Sep 26.
Transforming growth factor-β-activated kinase 1 (TAK1) is a mitogen-activated protein 3-kinase and an AMP-activated protein kinase (AMPK) kinase in some cell types. Although TAK1(-/-) mice display defects in developmental vasculogenesis, the role of TAK1 in endothelial cells has not been investigated in detail.
TAK1 downregulation (small interfering RNA) in human endothelial cells attenuated proliferation without inducing apoptosis and diminished endothelial cell migration, as well as tube formation. Cytokine- and vascular endothelial growth factor (VEGF)-induced endothelial cell sprouting in a modified spheroid assay were abrogated by TAK1 downregulation. Moreover, VEGF-induced endothelial sprouting was impaired in aortic rings from mice lacking TAK1 in endothelial cells (TAK(ΔEC)). TAK1 inhibition and downregulation also inhibited VEGF-stimulated phosphorylation of several kinases, including AMPK. Proteomic analyses revealed that superoxide dismutase 2 (SOD2) expression was reduced in TAK1-deficient endothelial cells, resulting in attenuated hydrogen peroxide production but increased mitochondrial superoxide production. Endothelial cell SOD2 expression was also attenuated by AMPK inhibition and in endothelial cells from AMPKα1(-/-) mice but was unaffected by inhibitors of c-Jun N-terminal kinase, p38, extracellular signal-regulated kinase 1/2, or phosphatidylinositol 3-kinase/Akt. Moreover, the impaired endothelial sprouting from TAK(ΔEC) aortic rings was abrogated in the presence of polyethylene glycol-SOD, and tube formation was normalized by the overexpression of SOD2. A similar rescue of angiogenesis was observed in polyethylene glycol-SOD-treated aortic rings from mice with endothelial cell-specific deletion of the AMPKα1.
These results establish TAK1 as an AMPKα1 kinase that regulates vascular endothelial growth factor-induced and cytokine-induced angiogenesis by modulating SOD2 expression and the superoxide anion:hydrogen peroxide balance.
转化生长因子-β激活激酶 1（TAK1）在某些细胞类型中是丝裂原激活蛋白 3-激酶和 AMP 激活蛋白激酶（AMPK）激酶。尽管 TAK1（-/-）小鼠在发育性血管发生中存在缺陷，但 TAK1 在血管内皮细胞中的作用尚未得到详细研究。
在人内皮细胞中下调 TAK1（小干扰 RNA）可减弱增殖而不诱导凋亡，并减少内皮细胞迁移和管形成。在改良的球体测定中，细胞因子和血管内皮生长因子（VEGF）诱导的内皮细胞出芽被 TAK1 下调所阻断。此外，缺乏内皮细胞中 TAK1（TAK（ΔEC））的小鼠的主动脉环中 VEGF 诱导的内皮出芽受损。TAK1 抑制和下调也抑制了包括 AMPK 在内的几种激酶的 VEGF 刺激磷酸化。蛋白质组学分析显示，TAK1 缺陷的内皮细胞中超氧化物歧化酶 2（SOD2）表达减少，导致过氧化氢产生减少但线粒体超氧产生增加。内皮细胞 SOD2 表达也被 AMPK 抑制和 AMPKα1（-/-）小鼠的内皮细胞减弱，但不受 c-Jun N 末端激酶、p38、细胞外信号调节激酶 1/2 或磷脂酰肌醇 3-激酶/Akt 抑制剂的影响。此外，TAK（ΔEC）主动脉环中受损的内皮出芽在存在聚乙二醇-SOD 的情况下被消除，并且 SOD2 的过表达使管形成正常化。在具有内皮细胞特异性 AMPKα1 缺失的小鼠的聚乙二醇-SOD 处理的主动脉环中观察到类似的血管生成挽救。
这些结果确立了 TAK1 作为 AMPKα1 激酶，通过调节 SOD2 表达和超氧阴离子：过氧化氢平衡来调节血管内皮生长因子诱导和细胞因子诱导的血管生成。
