Nagarkatti D S, Sha'afi R I
Department of Pharmacology, University of Connecticut, Health Center, Farmington, CT, USA.
J Mol Cell Cardiol. 1998 Aug;30(8):1651-64. doi: 10.1006/jmcc.1998.0733.
The current study focuses on the role of p38 MAP kinase in response to acute preconditioning stimuli and ischemia. Exposure of the rat myoblast cell line H9C2 to preconditioning stimuli, viz. brief duration of ischemia (metabolic inhibition) and adenosine, led to activation of p38 MAP kinase. The protective preconditioning effect of these stimuli against lethal ischemic insult was abolished in the presence or p38 MAP kinase inhibitor SB 203580 but not in the presence of MEK inhibitor PD 98509. Phorbol myristate acetate, PMA, which activates protein kinase C, PKC, activates p38 MAP kinase. and this activation is inhibited by PKC inhibitor G. 6850. The preconditioning effect of PMA was abolished by SB 203580 and also by protein kinase C inhibitor Go 6850. This indicates that the protective action of preconditioning by PKC is mediated via activation of p38 MAP kinase. Paradoxically, the presence of SB 203580 and Go 6850 during the lethal stress protected the cells against cell death. The mode of cell death in this study whether necrotic or apoptotic has not been established. Lethal ischemic stress activates p38 MAP kinase. Preconditioning the cells decreases the activation of p38 MAP kinase in response to the second lethal stress. These findings highlight the role of p38 MAP kinase in ischemic preconditioning v ischemia. Furthermore, our findings in an in vitro model using a proliferating cell line indicate that the duration and/or intensity of stimuli activating p38 kinase probably determines whether it would play a beneficial v deleterious role in cell survival in response to stress.
当前的研究聚焦于p38丝裂原活化蛋白激酶在急性预处理刺激和缺血反应中的作用。将大鼠成肌细胞系H9C2暴露于预处理刺激，即短暂的缺血（代谢抑制）和腺苷，会导致p38丝裂原活化蛋白激酶的激活。在存在p38丝裂原活化蛋白激酶抑制剂SB 203580的情况下，这些刺激对致死性缺血损伤的保护性预处理作用被消除，但在存在MEK抑制剂PD 98509时则不会。佛波酯肉豆蔻酸酯（PMA）可激活蛋白激酶C（PKC），进而激活p38丝裂原活化蛋白激酶，而这种激活可被PKC抑制剂G. 6850抑制。SB 203580以及蛋白激酶C抑制剂Go 6850均可消除PMA的预处理作用。这表明PKC介导的预处理保护作用是通过激活p38丝裂原活化蛋白激酶来实现的。矛盾的是，在致死性应激期间存在SB 203580和Go 6850可保护细胞免于死亡。本研究中细胞死亡的方式（坏死或凋亡）尚未确定。致死性缺血应激会激活p38丝裂原活化蛋白激酶。对细胞进行预处理可降低其在第二次致死性应激反应中p38丝裂原活化蛋白激酶的激活。这些发现突出了p38丝裂原活化蛋白激酶在缺血预处理与缺血过程中的作用。此外，我们在使用增殖细胞系的体外模型中的发现表明，激活p38激酶的刺激的持续时间和/或强度可能决定其在应激反应中对细胞存活是发挥有益还是有害作用。
