CaMKII inhibition mitigates ischemia/reperfusion-elicited calpain activation and the damage to membrane skeleton proteins in isolated rat hearts.

Ling-Heng Kong, Xiao-Ming Gu, Feng Wu, Zhen-Xiao Jin, Jing-Jun Zhou

Biochemical and biophysical research communications 2017 Sep 23

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Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been implicated in myocardial ischemia/reperfusion (IR) injury. The aim of this study was to determine the effect of CaMKII on the damage to membrane skeleton proteins, which is an important cause of IR injury. Isolated rat hearts were subjected to 45-min global ischemia/2-h reperfusion. Both KN-62 and KN-93 were used to inhibit CaMKII. Compared with controls, the hearts in the IR group exhibited remarkable myocardial injury area, LDH release, cell apoptosis and contractile dysfunction, along with an increase in the phosphorylation of CaMKII and its substrate phospholamban. Treatment with either KN-62 or KN-93 mitigated both the heart injury and the phosphorylation of CaMKII and phospholamban. The analysis of cell skeleton proteins revealed that IR injury resulted in an increase in the 150-kDa fragments resulting from the degradation of α-fodrin and dystrophin translocating from the sarcolemmal membrane to the cytosol and a decrease in the 220-kDa isoform of ankyrin-B. As expected, Evans blue dye staining showed an increase in membrane permeability or membrane rupture in the IR group. All of these alterations were alleviated by treatment with either KN-62 or KN-93. In addition, both KN-62 and KN-93 blocked the activity and membrane recruitment of calpain, a key protease responsible for destroying cell skeleton proteins during IR injury. In conclusion, our data provide evidence that damage to membrane skeleton proteins via calpain is a destructive downstream event of CaMKII activation in the setting of myocardial IR injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Citation

Ling-Heng Kong, Xiao-Ming Gu, Feng Wu, Zhen-Xiao Jin, Jing-Jun Zhou. CaMKII inhibition mitigates ischemia/reperfusion-elicited calpain activation and the damage to membrane skeleton proteins in isolated rat hearts. Biochemical and biophysical research communications. 2017 Sep 23;491(3):687-692