Upregulation of CaMKIIδ during ischaemia–reperfusion is associated with reperfusion-induced arrhythmias and mechanical dysfunction of the rat heart: involvement of sarcolemmal Ca2+-cycling proteins

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Abstract

Although Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIδ) has been implicated in development of different phenotypes of myocardial ischaemia-reperfusion injury, its involvement in arrhythmogenesis and cardiac stunning is not sufficiently elucidated. Moreover, the mechanisms by which CaMKIIδ mediates disturbances in excitation-contraction coupling, are not exactly known. To investigate this, KN-93 (0.5 µmol/L), a CaMKII inhibitor, was administered before induction of global ischaemia and reperfusion in isolated Langendorff-perfused rat hearts. Expression of CaMKIIδ and the sarcollemal Ca(2+)-cycling proteins, known to be activated during reperfusion, was analyzed using immunoblotting. KN-93 reduced reperfusion-induced ectopic activity and the incidence of ventricular fibrillation. Likewise, the severity of arrhythmias was lower in KN-treated hearts. During the pre-ischaemia phase, neither inotropic nor chronotropic effects were elicited by KN-93, whereas post-ischaemic contractile recovery was significantly improved. Ischaemia-reperfusion increased the expression of CaMKIIδ and sodium-calcium exchanger (NCX1) proteins without any influence on the protein content of alpha 1c, a pore-forming subunit of L-type calcium channels (LTCCs). On the other hand, inhibition of CaMKII normalized changes in the expression of CaMKIIδ and NCX1. Taken together, CaMKIIδ seems to regulate its own turnover and to be an important component of cascade integrating NCX1, rather than LTCCs that promote ischaemia-reperfusion-induced contractile dysfunction and arrhythmias.

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