Circ Res

RationaleCa2+/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.ObjectiveTo assess the contribution of CaMKII\u3b4 to the development of inflammation, infarct and ventricular dysfunction following in vivo I/R and define early cardiomyocyte-autonomous events regulated by CaMKII\u3b4 using cardiac-specific knockout (KO) mice.Methods and ResultsWild-type (WT) and CaMKII\u3b4 KO mice were subjected to in vivo I/R by occlusion of the left anterior descending (LAD) artery for 1-hr followed by reperfusion for various times. CaMKII\u3b4 deletion protected the heart against I/R damage as evidenced by decreased infarct size, attenuated apoptosis and improved functional recovery. CaMKII\u3b4 deletion also attenuated I/R induced inflammation and upregulation of NF-\u3baB target genes. Further studies demonstrated that I/R rapidly increases CaMKII activity, leading to NF-\u3baB activation within minutes of reperfusion. Experiments using cyclosporine A and cardiac-specific CaMKII\u3b4 knockout mice indicate that NF-\u3baB activation is initiated independent of necrosis and within cardiomyocytes. Expression of activated CaMKII in cardiomyocytes lead to I kappa B kinase (IKK) phosphorylation and concomitant increases in nuclear p65. Experiments using an IKK inhibitor support the conclusion that this is a proximal site of CaMKII-mediated NF-\u3baB activation.ConclusionsThis is the first study demonstrating that CaMKII\u3b4 mediates NF-\u3baB activation in cardiomyocytes following in vivo I/R and suggests that CaMKII\u3b4 serves to trigger, as well as to sustain subsequent changes in inflammatory gene expression that contribute to myocardial I/R damage.P01HL098053/HL/NHLBI NIH HHS/United StatesP01 HL080101/HL/NHLBI NIH HHS/United States8UL1TR000100-03/TR/NCATS NIH HHS/United States1U54HK08460-01/HK/PHITPO CDC HHS/United StatesT32 GM007752/GM/NIGMS NIH HHS/United StatesUL1 TR000100/TR/NCATS NIH HHS/United StatesHL080101/HL/NHLBI NIH HHS/United StatesP01 HL098053/HL/NHLBI NIH HHS/United States2014-03-15T00:00:00Z23388157PMC3673710vault:208