Intracellular Acidosis-Activated p38 MAPK & Hypoxia

P38丝裂原活化蛋白激酶(MAPK)的激活在细胞对多种应激信号的反应中起着核心作用。在心脏中，增强的p38MAPK信号与心脏缺氧和缺血损伤有关。然而，低氧诱导p38 MAPK激活的机制仍然不清楚。我们研究了成年大鼠心肌细胞缺氧时p38MAPK的激活情况。在这里，我们报道了低氧导致细胞内酸化和p38MAPK的激活，并且低氧诱导的p38MAPK信号可以通过中和细胞内pH而完全被取消，而细胞内酸化本身(细胞内pH和7.0)本身明显地增强了p38MAPK的激活，但不能激活ERK1/2和JNK。此外，抑制p38MAPK可保护心肌细胞免受缺氧性细胞死亡，提示酸中毒诱导的p38MAPK信号转导通路在缺氧性细胞损伤和细胞死亡中起重要作用。这些结果首次证明，细胞内酸中毒是低氧激活的p38MAPK信号通路以及随后的缺氧性心肌细胞损伤和死亡的必要和充分的环节。

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.