CaMKIIδ splice variants exert differential effects on heart failure development and myocardial ischemia/reperfusion injury (652.14)

Mice that lack CaMKIIδ (KO) are significantly protected from the development of myocardial damage following ischemia reperfusion (I/R). Cardioprotection in KO animals was associated with the loss of NF‐κB‐mediated inflammatory responses. CaMKIIδ is alternatively spliced in the heart to generate the CaMKIIδB and δC subtypes. In vitro data also suggest that δC is deleterious while δB may be cardioprotective. Furthermore, mice expressing δC rapidly and spontaneously progress to heart failure and death while those expressing δB have a milder phenotype. We postulated that CaMKIIδB and δC play opposing roles in response to I/R injury. Mice expressing CaMKIIδB and δC were subjected to global ischemia in the Langendorff mode for 25 minutes followed by reperfusion for various times. CaMKII activation and substrate phosphorylation were assessed by western blot. Subcellular fractionation was performed to determine compartment‐specific CaMKII activation. Infarct size was used as a measure of myocardial injury. I/R led to activation of CaMKIIδC but not δB in the cytosolic compartment. IκB‐Kinase (IKK) phosphorylation was increased in mice expressing CaMKIIδC but not in those expressing δB. Mice expressing δC showed large infarcts compared to WT, while mice expressing CaMKIIδB show greatly diminished infarct formation following I/R. The observation that pharmacological inhibition of IKK mitigated the deleterious effects of δC overexpression suggests that selective activation of CaMKIIδC in the cytosol and subsequent activation of inflammatory signaling contributes to I/R injury.