Miyawaki Takahiro, Mashiko Toshihiro, Ofengeim Dimitry, Flannery Richard J, Noh Kyung-Min, Fujisawa Sho, Bonanni Laura, Bennett Michael V L, Zukin R Suzanne, Jonas Elizabeth A
Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4892-7. doi: 10.1073/pnas.0800628105. Epub 2008 Mar 17.
Transient forebrain or global ischemia induces delayed neuronal death in vulnerable CA1 pyramidal cells with many features of apoptosis. A brief period of ischemia, i.e., ischemic preconditioning, affords robust protection of CA1 neurons against a subsequent more prolonged ischemic challenge. Here we show that preconditioning acts via PI3K/Akt signaling to block the ischemia-induced cascade involving mitochondrial translocation of Bad, assembly of Bad with Bcl-x(L), cleavage of Bcl-x(L) to form its prodeath fragment, DeltaN-Bcl-x(L), activation of large-conductance channels in the mitochondrial outer membrane, mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), caspase activation, and neuronal death. These findings show how preconditioning acts to prevent the release of cytochrome c and Smac/DIABLO from mitochondria and to preserve the integrity of the mitochondrial membrane. The specific PI3K inhibitor LY294002 administered in vivo 1 h before or immediately after ischemia or up to 120 h later significantly reverses preconditioning-induced protection, indicating a requirement for sustained PI3K signaling in ischemic tolerance. These findings implicate PI3K/Akt signaling in maintenance of the integrity of the mitochondrial outer membrane.
短暂性前脑或全脑缺血会在易损的CA1锥体细胞中诱导延迟性神经元死亡，具有许多凋亡特征。短暂的缺血期，即缺血预处理，能为CA1神经元提供强大的保护，使其免受随后更长时间的缺血挑战。我们在此表明，预处理通过PI3K/Akt信号传导发挥作用，以阻断缺血诱导的级联反应，该反应涉及Bad的线粒体易位、Bad与Bcl-x(L)的组装、Bcl-x(L)裂解形成其促死亡片段DeltaN-Bcl-x(L)、线粒体外膜大电导通道的激活、细胞色素c和Smac/DIABLO（第二线粒体衍生的半胱天冬酶激活剂/低pI的直接IAP结合蛋白）的线粒体释放、半胱天冬酶激活以及神经元死亡。这些发现揭示了预处理如何防止细胞色素c和Smac/DIABLO从线粒体释放，并维持线粒体膜的完整性。在缺血前1小时、缺血后立即或长达120小时后体内给予特异性PI3K抑制剂LY294002，可显著逆转预处理诱导的保护作用，表明缺血耐受中需要持续的PI3K信号传导。这些发现表明PI3K/Akt信号传导与线粒体外膜完整性的维持有关。
