Myocardial death and dysfunction after ischemia-reperfusion injury require CaMKIIδ oxidation.
Myocardial death and dysfunction after ischemia-reperfusion injury require CaMKIIδ oxidation.
复制标题
缺血再灌注损伤后的心肌死亡和功能障碍需要 CaMKIIδ 氧化。
DOI：
10.1038/s41598-019-45743-6
复制
发表时间：
2019
影响因子：
4.6
通讯作者：
Anderson,MarkE
中科院分区：
文献类型：
--
作者：
Wu,Yuejin;Wang,Qinchuan;Feng,Ning;Granger,JonathanM;Anderson,MarkE
活性氧（ROS）在缺血再灌注（I/R）损伤过程中参与心肌死亡，但缺乏将ROS与心脏损伤联系起来的分子通路的详细知识。Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKIIδ）的激活与心肌死亡有关，CaMKII可被ROS（ox-CaMKII）通过氧化调节结构域甲硫氨酸（Met 281/282）激活。我们检查了小鼠I/R损伤，其中通过敲入用缬氨酸取代调节结构域甲硫氨酸（MMVV）使CaMK II δ对ROS活化具有抗性。我们发现与WT对照组相比，MMVVin体内和体外I/R损伤后24小时心肌死亡减少，左心室功能改善。ATP敏感性K+通道（KATP）电流的丧失导致I/R损伤，CaMKII促进KATP从心肌细胞膜隔离。H_2O_2可显著降低WT心室肌细胞KATP电流密度，但在MMVV中无此作用，表明ox-CaMKII可降低KATP利用率。综上所述，这些发现支持这样的观点，即ox-CaMKII和KATP是通过ROS促进I/R损伤的信号传导轴的组分。
Reactive oxygen species (ROS) contribute to myocardial death during ischemia-reperfusion (I/R) injury, but detailed knowledge of molecular pathways connecting ROS to cardiac injury is lacking. Activation of the Ca2+/calmodulin-dependent protein kinase II (CaMKIIδ) is implicated in myocardial death, and CaMKII can be activated by ROS (ox-CaMKII) through oxidation of regulatory domain methionines (Met281/282). We examined I/R injury in mice where CaMKIIδ was made resistant to ROS activation by knock-in replacement of regulatory domain methionines with valines (MMVV). We found reduced myocardial death, and improved left ventricular function 24 hours after I/R injury in MMVVin vivoandin vitrocompared to WT controls. Loss of ATP sensitive K+channel (KATP) current contributes to I/R injury, and CaMKII promotes sequestration of KATP from myocardial cell membranes. KATP current density was significantly reduced by H2O2in WT ventricular myocytes, but not in MMVV, showing ox-CaMKII decreases KATP availability. Taken together, these findings support a view that ox-CaMKII and KATP are components of a signaling axis promoting I/R injury by ROS.