Submitted on November 1, 2008
Revised on June 9, 2009
Accepted on June 9, 2009
Calcium/calmodulin-dependent protein kinase II mediates cardioprotection of intermittent hypoxia against ischemic-reperfusion-induced cardiac dysfunction
Zhuo Yu1, Zhi-Hua Wang1, and Huang-Tian Yang1*
1 Institute of Health Sciences
* To whom correspondence should be addressed. E-mail: htyang{at}sibs.ac.cn.
Intermittent high-altitude (IHA) hypoxia-induced cardioprotection against ischemia-reperfusion (I/R) injury is associated with preservation of sarcoplasmic reticulum (SR) function. Although Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phosphatase are known to modulate the function of cardiac SR under physiological conditions, the status of SR CaMKII and phosphatase during I/R in the hearts from IHA hypoxic rats is unknown. In the present study, we determined SR and cytosolic CaMKII activity during preischemia and I/R (30-min/30-min) in perfused hearts from normoxic and IHA hypoxic rats. The left ventricular contractile recovery, SR CaMKII activity as well as phosphorylation of phospholamban (PLB) at Thr17, and Ca2+/calmodulin-dependent SR Ca2+-uptake activity were depressed in the I/R hearts from normoxic rats, while these changes were prevented in the hearts from IHA hypoxic rats. Such beneficial effects of IHA hypoxia were lost upon treating the hearts with a specific CaMKII inhibitor KN-93. I/R also depressed cytosolic CaMKII and SR phosphatase activity but these alterations remained unchanged in IHA hypoxic group. Furthermore, we found autophosphorylation at threonine 287, which confers Ca2+/CaM-independent activity, was not altered by I/R in both groups. These findings indicate that preservation of SR CaMKII activity plays an important role in IHA hypoxia-induced cardioprotection against I/R injury via maintaining SR Ca2+-uptake activity.
