| First Author | Ling H | Year | 2013 |
| Journal | Circ Res | Volume | 112 |
| Issue | 6 | Pages | 935-44 |
| PubMed ID | 23388157 | Mgi Jnum | J:245860 |
| Mgi Id | MGI:5921356 | Doi | 10.1161/CIRCRESAHA.112.276915 |
| Citation | Ling H, et al. (2013) Ca2+/Calmodulin-dependent protein kinase II delta mediates myocardial ischemia/reperfusion injury through nuclear factor-kappaB. Circ Res 112(6):935-44 |
| abstractText | RATIONALE: Ca(2+)/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 CaMKIIdelta to the development of inflammation, infarct, and ventricular dysfunction after in vivo I/R and define early cardiomyocyte-autonomous events regulated by CaMKIIdelta using cardiac-specific knockout mice. METHODS AND RESULTS: Wild-type and CaMKIIdelta 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. CaMKIIdelta deletion protected the heart against I/R damage as evidenced by decreased infarct size, attenuated apoptosis, and improved functional recovery. CaMKIIdelta deletion also attenuated I/R-induced inflammation and upregulation of nuclear factor-kappaB (NF-kappaB) target genes. Further studies demonstrated that I/R rapidly increases CaMKII activity, leading to NF-kappaB activation within minutes of reperfusion. Experiments using cyclosporine A and cardiac-specific CaMKIIdelta knockout mice indicate that NF-kappaB activation is initiated independent of necrosis and within cardiomyocytes. Expression of activated CaMKII in cardiomyocytes leads to IkappaB kinase phosphorylation and concomitant increases in nuclear p65. Experiments using an IkappaB kinase inhibitor support the conclusion that this is a proximal site of CaMKII-mediated NF-kappaB activation. CONCLUSIONS: This is the first study demonstrating that CaMKIIdelta mediates NF-kappaB activation in cardiomyocytes after in vivo I/R and suggests that CaMKIIdelta serves to trigger, as well as to sustain subsequent changes in inflammatory gene expression that contribute to myocardial I/R damage. |
