Zhang Xuchen, Shan Peiying, Alam Jawed, Davis Roger J, Flavell Richard A, Lee Patty J
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
J Biol Chem. 2003 Jun 13;278(24):22061-70. doi: 10.1074/jbc.M301858200. Epub 2003 Apr 10.
Carbon monoxide is protective in ischemia-reperfusion organ injury, but the precise mechanisms remain elusive. We have recently shown that low levels of exogenous carbon monoxide (CO) utilize p38 MAPK and attenuate caspase 3 activity to exert an antiapoptotic effect during lung ischemia-reperfusion injury. Our current data demonstrate that CO activates the p38alpha MAPK isoform and the upstream MAPK kinase MKK3 to modulate Fas/Fas ligand expression; caspases 3, 8, and 9; mitochondrial cytochrome c release; Bcl-2 proteins; and poly(ADP-ribose) polymerase cleavage. We correlate our in vitro findings with in vivo studies using MKK3-deficient and Fas-deficient mice. Taken together, our data are the first to demonstrate that CO has an antiapoptotic effect by inhibiting Fas/Fas ligand, caspases, proapoptotic Bcl-2 proteins, and cytochrome c release via the MKK3/p38alpha MAPK pathway.
一氧化碳对缺血再灌注器官损伤具有保护作用，但其确切机制仍不清楚。我们最近发现，低水平的外源性一氧化碳（CO）通过利用p38丝裂原活化蛋白激酶（MAPK）并减弱半胱天冬酶3的活性，在肺缺血再灌注损伤期间发挥抗凋亡作用。我们目前的数据表明，CO激活p38α MAPK亚型和上游的MAPK激酶MKK3，以调节Fas/Fas配体的表达；半胱天冬酶3、8和9；线粒体细胞色素c的释放；Bcl-2蛋白；以及聚（ADP-核糖）聚合酶的裂解。我们将体外研究结果与使用MKK3缺陷型和Fas缺陷型小鼠的体内研究进行了关联。综上所述，我们的数据首次证明，CO通过MKK3/p38α MAPK途径抑制Fas/Fas配体、半胱天冬酶、促凋亡Bcl-2蛋白和细胞色素c的释放，从而发挥抗凋亡作用。
