Ca2+/Calmodulin-Dependent Protein Kinase II δ Mediates Myocardial Ischemia/Reperfusion Injury Through Nuclear Factor-κB

Rationale: Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been implicated as a maladaptive mediator of cardiac ischemic injury. We hypothesized that the inflammatory response associated with in vivo ischemia/reperfusion (I/R) is initiated through CaMKII signaling. Objective: To assess the contribution of CaMKII delta to the development of inflammation, infarct, and ventricular dysfunction after in vivo I/R and define early cardiomyocyte-autonomous events regulated by CaMKII delta using cardiac-specific knockout mice. Methods and Results: Wild-type and CaMKII delta knockout mice were subjected to in vivo I/R by occlusion of the left anterior descending artery for 1 hour followed by reperfusion for various times. CaMKII delta deletion protected the heart against I/R damage as evidenced by decreased infarct size, attenuated apoptosis, and improved functional recovery. CaMKII delta deletion also attenuated I/R-induced inflammation and upregulation of nuclear factor-kappa B (NF-kappa B) target genes. Further studies demonstrated that I/R rapidly increases CaMKII activity, leading to NF-kappa B activation within minutes of reperfusion. Experiments using cyclosporine A and cardiac-specific CaMKII delta knockout mice indicate that NF-kappa B activation is initiated independent of necrosis and within cardiomyocytes. Expression of activated CaMKII in cardiomyocytes leads to I kappa B kinase phosphorylation and concomitant increases in nuclear p65. Experiments using an I kappa B kinase inhibitor support the conclusion that this is a proximal site of CaMKII-mediated NF-kappa B activation. Conclusions: This is the first study demonstrating that CaMKII delta mediates NF-kappa B activation in cardiomyocytes after in vivo I/R and suggests that CaMKII delta serves to trigger, as well as to sustain subsequent changes in inflammatory gene expression that contribute to myocardial I/R damage. (Circ Res. 2013;112:935-944.)