Calcium/calmodulin-dependent protein kinase IV limits organ damage in hepatic ischemia-reperfusion injury through induction of autophagy
Calcium/calmodulin-dependent protein kinase IV limits organ damage in hepatic ischemia-reperfusion injury through induction of autophagy
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DOI：
10.1152/ajpgi.00051.2012
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发表时间：
2012-07-01
影响因子：
4.5
通讯作者：
Tsung, Allan
中科院分区：
文献类型：
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作者：
Evankovich, John;Zhang, Ruilin;Tsung, Allan
Evankovich J，张荣，红衣主教JS，张L，陈J，黄H，Beer-Stolz D，Billiar tr，Rosengart MR，Tung A。钙/钙调素依赖的蛋白激酶IV通过诱导自噬来限制肝脏缺血再灌注损伤中的器官损伤。Am J Physiol胃肠病肝生理学303：G189-G198,2012。2012年5月10日首次出版；DOI：10.1152/ajpgi.00051.2012-无菌炎性侮辱，如缺血再灌注(I/R)损伤，由致病因素引起，包括损伤相关的分子模式信号、天然免疫的激活和促炎细胞因子的上调。同时，一些保护性或生存性途径也被激活，而末端器官损伤的程度最终由这两个系统之间的平衡决定。在肝脏I/R中，钙/钙调蛋白依赖性蛋白激酶(CaMK)家族的成员已知被激活，但它们的个体作用在很大程度上是未知的。在这项研究中，我们证明了CaMK成员CaMKIV通过激活肝细胞自噬的生存途径在肝脏I/R中具有保护作用。CaMKIV基因敲除小鼠在I/R后出现明显更严重的器官损伤，并缺乏肝细胞自噬信号。用雷帕霉素恢复自噬信号可将CaMKIV基因敲除小鼠的器官损伤降低到野生型水平。在体外，我们发现CaMKIV激活诱导小鼠肝细胞自噬，并且CaMKIV激活保护肝细胞免受氧化应激诱导的细胞死亡。综上所述，保护性自噬信号通路有助于减轻I/R后的器官损伤，并受肝细胞内CaMKIV信号的激活调节。
Evankovich J, Zhang R, Cardinal JS, Zhang L, Chen J, Huang H, Beer-Stolz D, Billiar TR, Rosengart MR, Tsung A. Calcium/calmodulin-dependent protein kinase IV limits organ damage in hepatic ischemia-reperfusion injury through induction of autophagy. Am J Physiol Gastrointest Liver Physiol 303: G189-G198, 2012. First published May 10, 2012; doi:10.1152/ajpgi.00051.2012.-Sterile inflammatory insults, such as ischemia-reperfusion (I/R) injury, result from pathogenic factors, including damage-associated molecular pattern signaling, activation of innate immunity, and upregulation of proinflammatory cytokines. At the same time, a number of protective, or prosurvival, pathways are also activated, and the extent of end-organ damage is ultimately determined by the balance between these two systems. In liver I/R, members of the calcium/calmodulin-dependent protein kinase (CaMK) family are known to be activated, but their individual roles are largely unknown. In this study, we show that one CaMK member, CaMKIV, is protective in hepatic I/R by activating the prosurvival pathway of autophagy in hepatocytes. CaMKIV knockout mice experience significantly worse organ damage after I/R and are deficient in hepatocyte autophagic signaling. Restoration of autophagic signaling with rapamycin reduces organ damage in CaMKIV knockout mice to wild-type levels. In vitro, we show that CaMKIV activation induces autophagy in mouse hepatocytes, and that CaMKIV activation protects hepatocytes from oxidative stress-induced cell death. In conclusion, the protective autophagic signaling pathway serves to reduce organ damage following I/R and is regulated by activation of CaMKIV signaling in hepatocytes.