Erickson Jeffrey R, Joiner Mei-ling A, Guan Xiaoqun, Kutschke William, Yang Jinying, Oddis Carmine V, Bartlett Ryan K, Lowe John S, O'Donnell Susan E, Aykin-Burns Nukhet, Zimmerman Matthew C, Zimmerman Kathy, Ham Amy-Joan L, Weiss Robert M, Spitz Douglas R, Shea Madeline A, Colbran Roger J, Mohler Peter J, Anderson Mark E
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1109, USA.
Cell. 2008 May 2;133(3):462-74. doi: 10.1016/j.cell.2008.02.048.
Calcium/calmodulin (Ca2+/CaM)-dependent protein kinase II (CaMKII) couples increases in cellular Ca2+ to fundamental responses in excitable cells. CaMKII was identified over 20 years ago by activation dependence on Ca2+/CaM, but recent evidence shows that CaMKII activity is also enhanced by pro-oxidant conditions. Here we show that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM. CaMKII is activated by angiotensin II (AngII)-induced oxidation, leading to apoptosis in cardiomyocytes both in vitro and in vivo. CaMKII oxidation is reversed by methionine sulfoxide reductase A (MsrA), and MsrA-/- mice show exaggerated CaMKII oxidation and myocardial apoptosis, impaired cardiac function, and increased mortality after myocardial infarction. Our data demonstrate a dynamic mechanism for CaMKII activation by oxidation and highlight the critical importance of oxidation-dependent CaMKII activation to AngII and ischemic myocardial apoptosis.
钙/钙调蛋白（Ca2+/CaM）依赖性蛋白激酶II（CaMKII）将细胞内Ca2+的增加与可兴奋细胞的基本反应联系起来。CaMKII在20多年前通过对Ca2+/CaM的激活依赖性被鉴定出来，但最近的证据表明，促氧化条件也能增强CaMKII的活性。在这里，我们表明，在没有Ca2+/CaM的情况下，成对调节结构域甲硫氨酸残基的氧化维持了CaMKII的活性。CaMKII被血管紧张素II（AngII）诱导的氧化激活，导致体外和体内心肌细胞凋亡。甲硫氨酸亚砜还原酶A（MsrA）可逆转CaMKII的氧化，MsrA基因敲除小鼠表现出过度的CaMKII氧化和心肌凋亡、心脏功能受损以及心肌梗死后死亡率增加。我们的数据证明了通过氧化激活CaMKII的动态机制，并强调了氧化依赖性CaMKII激活对AngII和缺血性心肌凋亡的至关重要性。
