Objectives: 

Aims of the study were: to investigate whether Ca2+-calmodulin-dependent protein kinase II delta underlies ischemia/reperfusion(I/R)-induced injury, such as contractile dysfunction, arrhythmias, and cell death, as well as the subcellular mechanisms involved. Furthermore, the role of oxidative stress in activation of CaMKII delta and associated processes were examined.

Materials: 

In isolated Langendorff-perfused rat hearts, a CaMKII inhibitor (KN-93, 0.5 micromol/L), was administered before induction of global 30-min I and during 10 min of 40-min R. Protein contents were analyzed by imunnoblotting (WB).

Results: 

CaMKII inhibition reduced reperfusion-induced ectopic activity; the incidence of ventricular fibrillation was decreased. Likewise, the total number of premature ventricular complexes and the severity of all arrhythmias were lower in the hearts treated with KN-93. During the pre-ischemia phase, neither inotropic nor chronotropic effects were elicited by a CaMKII inhibitor, whereas post-ischaemic contractile recovery was significantly improved. Expression of CaMKII delta and sodium-calcium exchanger proteins was increased upon I/R, while CaMKII inhibition reversed these changes and reduced phosphorylation of CaMKII delta without any influence on the levels of a pore-forming subunit of L-type calcium channel. The increased content of proteins of the intrinsic apoptotic cell death (capsase-9, cyt C, casp-3) in the I/R hearts was normalized by a CaMKII inhibitor. Higher Bcl-2/Bax ratio in the treated hearts indicated increased cardiomyocytes viability. In addition, CaMKII inhibition decreased oxidative stress in the I/R hearts evidenced by a lower expression of NADPH oxidase, with no influence on catalase levels.

Conclusions: 

CaMKII delta seems to regulate its own turnover and to be an important component of cascades leading to dysregulation of excitation-contraction coupling, intrinsic apoptosis and oxidative stress, which in turn underlie cardiac injury due to I and R. VEGA SR 2/0054/11, 1/0638/12 and APVV-0523-10.