Author/Authors :
Jeffrey R. Erickson، نويسنده , , Mei-ling A. Joiner، نويسنده , , Xiaoqun Guan، نويسنده , , William Kutschke، نويسنده , , Jinying Yang، نويسنده , , Carmine V. Oddis، نويسنده , , Ryan K. Bartlett، نويسنده , , John S. Lowe، نويسنده , , Susan E. OʹDonnell، نويسنده , , Nukhet Aykin-Burns، نويسنده , , Matthew C. Zimmerman، نويسنده , , Kathy Zimmerman، نويسنده , , Amy-Joan L. Ham، نويسنده , , Robert M. Weiss، نويسنده , , Douglas R. Spitz، نويسنده , , Johannes W. Hell and Madeline A. Shea، نويسنده , , Roger J. Colbran، نويسنده , , Peter J. Mohler، نويسنده , , Mark E. Anderson، نويسنده ,
Abstract :
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.
