Protein phosphatase 2A-mediated cross-talk between p38 MAPK and ERK in apoptosis of cardiac myocytes
Protein phosphatase 2A-mediated cross-talk between p38 MAPK and ERK in apoptosis of cardiac myocytes
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DOI：
10.1152/ajpheart.01050.2003
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发表时间：
2004-06-01
影响因子：
4.8
通讯作者：
Hofmann, PA
中科院分区：
文献类型：
--
作者：
Liu, QH;Hofmann, PA
有丝分裂原活化蛋白激酶（MAPK）在氧化应激诱导的心肌细胞凋亡中起着不同的调节作用。本研究探讨了p38 MAPK与细胞外信号调节激酶（ERK）通路之间的相互作用在心室肌细胞中的调节和功能作用。我们证明，SB-203580和SB-239063抑制p38 MAPK可增强H2 O2刺激的ERK磷酸化，而亚砷酸钠预激活p38 MAPK可降低H2 O2刺激的ERK磷酸化。此外，用蛋白磷酸酶2A（PP 2A）抑制剂冈田酸和fostriecin预处理细胞增加了基础和H2 O2刺激的ERK磷酸化。我们还发现，PP 2A与ERK和MAPK/ERK（MEK）在心室肌细胞中免疫共沉淀，H2 O2增加ERK相关的PP 2A活性，抑制p38 MAPK可阻断这种活性。最后，H2 O2诱导的细胞凋亡被p38 MAPK或PP 2A抑制减弱，而被MEK抑制增强。因此，本研究表明，p38 MAPK激活减少H2 O2诱导的ERK激活通过PP 2A依赖的机制在心室肌细胞。这代表了一种新的细胞机制，允许两种相反的MAPK途径相互作用并在氧化应激期间对细胞凋亡进行精细调节。
Mitogen-activated protein kinases (MAPKs) play different regulatory roles in signaling oxidative stress-induced apoptosis in cardiac ventricular myocytes. The regulation and functional role of cross-talk between p38 MAPK and extracellular signal-regulated kinase (ERK) pathways were investigated in cardiac ventricular myocytes in the present study. We demonstrated that inhibition of p38 MAPK with SB-203580 and SB-239063 enhanced H2O2-stimulated ERK phosphorylation, whereas preactivation of p38 MAPK with sodium arsenite reduced H2O2-stimulated ERK phosphorylation. In addition, pretreatment of cells with the protein phosphatase 2A (PP2A) inhibitors okadaic acid and fostriecin increased basal and H2O2-stimulated ERK phosphorylation. We also found that PP2A coimmunoprecipitated with ERK and MAPK/ERK (MEK) in cardiac ventricular myocytes, and H2O2 increased the ERK-associated PP2A activity that was blocked by inhibition of p38 MAPK. Finally, H2O2-induced apoptosis was attenuated by p38 MAPK or PP2A inhibition, whereas it was enhanced by MEK inhibition. Thus the present study demonstrated that p38 MAPK activation decreases H2O2-induced ERK activation through a PP2A-dependent mechanism in cardiac ventricular myocytes. This represents a novel cellular mechanism that allows for interaction of two opposing MAPK pathways and fine modulation of apoptosis during oxidative stress.