Li C, Hu Y, Sturm G, Wick G, Xu Q
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.
Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):E1-9. doi: 10.1161/01.atv.20.3.e1.
p38, a subfamily of the mitogen-activated protein kinases (MAPKs), is a crucial signal transducer between a variety of extracellular stimuli and gene expression in mammalian cells. This kinase is activated in cultured cells stimulated by heat shock, osmotic stress, and proinflammatory cytokines, but a similar activation of p38 MAPKs in vascular smooth muscle cells (SMCs) stimulated by mechanical stress has yet to be studied. We studied signal pathways leading to time- and strength-dependent p38 activation in rat SMCs in response to cyclic strain stress. p38 phosphorylation in stressed SMCs showed maximal activation at 10 minutes. This activation was significantly inhibited by pretreatment of the SMCs with pertussis toxin, a G-protein antagonist, and enhanced by treatment with suramin, a growth factor receptor antagonist, but opposite effects in the activation of extracellular signal-regulated kinases stimulated by mechanical forces were found. p38 activation was markedly reduced in stressed SMCs after protein kinase C depletion. Interestingly, SMC lines stably expressing dominant-negative ras (ras N17) or rac1 (rac1 N17) almost abolished p38 phosphorylation induced by cyclic strain stress. When p38 activation was inhibited by the specific inhibitor SB 202190, SMC migration, determined in a Boyden chamber in response to stimulation with platelet-derived growth factor-BB, and SMC proliferation, stimulated by cyclic strain stress, were abrogated. Thus, we provide the first evidence that cyclic strain stress rapidly activates p38 MAPKs via activation of protein kinase C ras/rac signal pathways, suggesting that p38 MAPKs are important signal transducers mediating the mechanical stress-induced cell responses essential for SMC migration and proliferation.
p38是丝裂原活化蛋白激酶（MAPK）的一个亚家族，是哺乳动物细胞中多种细胞外刺激与基因表达之间的关键信号转导分子。该激酶在受到热休克、渗透压应激和促炎细胞因子刺激的培养细胞中被激活，但机械应激刺激血管平滑肌细胞（SMC）时p38 MAPK的类似激活情况尚未得到研究。我们研究了大鼠SMC中响应周期性应变应激导致p38时间和强度依赖性激活的信号通路。应激SMC中的p38磷酸化在10分钟时显示出最大激活。用百日咳毒素（一种G蛋白拮抗剂）预处理SMC可显著抑制这种激活，而用苏拉明（一种生长因子受体拮抗剂）处理则可增强这种激活，但在机械力刺激下细胞外信号调节激酶的激活中发现了相反的作用。蛋白激酶C耗竭后，应激SMC中的p38激活明显降低。有趣的是，稳定表达显性负性ras（ras N17）或rac1（rac1 N17）的SMC系几乎消除了周期性应变应激诱导的p38磷酸化。当用特异性抑制剂SB 202190抑制p38激活时，在博伊登小室中测定的血小板衍生生长因子-BB刺激下的SMC迁移以及周期性应变应激刺激下的SMC增殖均被消除。因此，我们提供了首个证据，即周期性应变应激通过激活蛋白激酶C ras/rac信号通路快速激活p38 MAPK，这表明p38 MAPK是介导机械应激诱导的细胞反应的重要信号转导分子，这些反应对于SMC迁移和增殖至关重要。
