CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect.

The present study investigated whether oxidative stress and Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure-volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100 mmHg) in C57BL/6N wild-type (WT) and CaMKII-double knockout mice (DKOCaMKII ). In snap-frozen WT hearts, force-pCa relationship, H2 O2 generation, CaMKII oxidation and phosphorylation of myofilament and Ca2+ handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H2 O2 generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end-diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKOCaMKII -hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca2+ concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac-myosin binding protein-C, myosin light chain and Ca2+ handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca2+ handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds.