Intracellular Acidosis-Activated p38 MAPK & Hypoxia

细胞内酸中毒激活的 p38 MAPK

• 批准号: 6969624
• 负责人: Rui-Ping Xiao
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6969624
• 关键词: acidosis; biological signal transduction; cardiac myocytes; enzyme activity; intracellular; laboratory rat; mitogen activated protein kinase; myocardial ischemia /hypoxia

Activation of p38 mitogen activated protein kinase (MAPK) plays a central role in cellular responses to a multitude of stress signals. In the heart, enhanced p38 MAPK signaling has been implicated in cardiac hypoxic and ischemic injury. However, the mechanism underlying hypoxia-induced p38 MAPK activation remains elusive. We investigated p38 MAPK activation during hypoxia in adult rat cardiomyocytes. Here, we reported that hypoxia leads to concurrent intracellular acidosis and activation of p38 MAPK, and that the hypoxia-induced p38 MAPK signaling can be fully abolished by neutralizing intracellular pH, whereas intracellular acidosis (intracellular pH<7.0) per se overtly augments activation of p38 MAPK but not ERK1/2 and JNK. Furthermore, inhibition of p38 MAPK protects myocytes against hypoxic cell death, suggesting that acidosis-evoked p38 MAPK signaling plays an important role in hypoxic cell injury and cell death. These results demonstrate, for the first time, that intracellular acidosis constitutes a necessary and sufficient link responsible for hypoxia-activated p38 MAPK signaling and the subsequent hypoxic cardiomyocyte injury and death.

p38 丝裂原激活蛋白激酶 (MAPK) 的激活在细胞对多种应激信号的反应中发挥着核心作用。在心脏中，增强的 p38 MAPK 信号传导与心脏缺氧和缺血性损伤有关。然而，缺氧诱导 p38 MAPK 激活的机制仍然难以捉摸。我们研究了成年大鼠心肌细胞缺氧期间 p38 MAPK 的激活。在此，我们报道缺氧会导致同时发生的细胞内酸中毒和 p38 MAPK 的激活，并且缺氧诱导的 p38 MAPK 信号传导可以通过中和细胞内 pH 值来完全消除，而细胞内酸中毒（细胞内 pH<7.0）本身会明显增强 p38 MAPK 的激活，但不会增强 ERK1/2 和 JNK 的激活。此外，抑制 p38 MAPK 可以保护心肌细胞免受缺氧细胞死亡，表明酸中毒诱发的 p38 MAPK 信号在缺氧细胞损伤和细胞死亡中发挥重要作用。这些结果首次证明，细胞内酸中毒是缺氧激活的 p38 MAPK 信号传导以及随后的缺氧心肌细胞损伤和死亡的必要且充分的环节。