Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in cardiac contractility and heart disease. However, the specific role of alternatively spliced variants of CaMKII in cardiac disease and apoptosis remains poorly explored. Here we report that the ␦B subunit of CaMKII (CaMKII␦B), which is the predominant nuclear isoform of calcium/calmodulin-dependent protein kinases in heart muscle, acts as an anti-apoptotic factor and is a novel target of the antineoplastic and cardiomyopathic drug doxorubicin (Dox (adriamycin)). Hearts of rats that develop cardiomyopathy following chronic treatment with Dox also show down-regulation of CaMKII␦B mRNA, which correlates with decreased cardiac function in vivo, reduced expression of sarcomeric proteins, and increased tissue damage associated with Dox cardiotoxicity. Overexpression of CaMKII␦B in primary cardiac cells inhibits Dox-mediated apoptosis and prevents the loss of the antiapoptotic protein Bcl-2. Specific silencing of CaMKII␦B by small interfering RNA prevents the formation of organized sarcomeres and decreases the expression of Bcl-2, which all mimic the effect of Dox. CaMKII␦B is required for GATA-4-mediated co-activation and binding to the Bcl-2 promoter. These results reveal that CaMKII␦B plays an essential role in cardiomyocyte survival and provide a mechanism for the protective role of CaMKII␦B. These results suggest that selective targeting of CaMKII in the nuclear compartment might represent a strategy to regulate cardiac apoptosis and to reduce Dox-mediated cardiotoxicity.

Ranolazine is an inhibitor of the late sodium current and, via this mechanism, decreases sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces angina, but there is little information on its effects in acute myocardial infarction. The aim of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial infarct size after ischemia/reperfusion in rabbits. Ten minutes before coronary artery occlusion (CAO), anesthetized rabbits were assigned to vehicle (n ϭ 15) or ranolazine (2 mg/kg i.v. bolus plus 60 g/kg/min i.v. infusion; n ϭ 15). Hearts received 60 min of CAO and 3 h of reperfusion. CAO caused LV dysfunction associated with necrosis. However, at the end of reperfusion, rabbits treated with ranolazine had better global LV ejection fraction (0.42 Ϯ 0.02 versus 0.33 Ϯ 0.02; p Ͻ 0.007) and stroke volume (1.05 Ϯ 0.08 versus 0.78 Ϯ 0.07 ml; p Ͻ 0.01) compared with vehicle. The fraction of the LV wall that was akinetic or dyskinetic was significantly less in the ranolazine group at 0.23 Ϯ 0.03 versus 0.34 Ϯ 0.03 in vehicle-treated group; p Ͻ 0.02. The ischemic risk region was similar in both groups; however, infarct size was significantly smaller in the treated group (44 Ϯ 5 versus 57 Ϯ 4% vehicle; p Ͻ 0.04). There were no significant differences among groups in heart rate, arterial pressure, LV end-diastolic pressure, or maximum-positive or -negative first time derivative of LV pressure (dP/dt). In conclusion, the results of this study show that ranolazine provides protection during acute myocardial infarction in this rabbit model of ischemia/reperfusion. Ranolazine treatment led to better ejection fraction, stroke volume and less wall motion abnormality after reperfusion, and less myocardial necrosis.

No abstract

No abstract