Abstract 18536: Camkii-δ Splice Variants Exert Differential Effects on Heart Failure Development and Myocardial Ischemia / Reperfusion Injury
Background: Ca2+/calmodulin-dependent kinase II-δ (CaMKII-δ) has been implicated in heart failure development and ischemia / reperfusion injury. It has been suggested that the most abundant cardiac isoforms, CaMKII-δb and CaMKII-δc, serve distinct and opposing roles on cardiomyocyte survival. We therefore evaluated their effects on heart failure development and myocardial ischemia reperfusion injury.
Methods: Mice with cardiac specific overexpression of the CaMKII-δb or CaMKII-δC, were crossbred with CaMKIIδ knockout (δ-KO) mice to generate mice that exclusively express CaMKII-δb (δb/KO) or CaMKII-δc (δc/KO). Cardiac mRNA profiling, longitudinal cardiac function, survival and the cardiac response to ischemia reperfusion injury were compared.
Results: Overexpression of CaMKII-δb and CaMKII-δc in the heart resulted in markedly different mRNA expression profile, with less than 10% overlapping genes. Loss of CaMKII-δb resulted in a more severe heart failure phenotype in δc/KO mice, as evidenced by accelerated development of left ventricular dysfunction and a marked reduction in survival compared to conventional CaMKII-δC transgenic mice. In contrast δb/KO mice only developed mild cardiac hypertrophy after 4 months. When challenged by ex vivo ischemia/reperfusion (I/R), δb/KO mice displayed a 75% reduction in infarct size, significantly greater than the reduction observed in KO mice lacking both splice variants. Conversely infarct formation was markedly increased in δc/KO mice (figure). These findings were recapitulated in functional recovery and LDH release. Studies with adult ventricular myocytes indicated that CaMKII-δb and δc have opposing roles in the response to oxidative stress.
Conclusion: CaMKII-delta splice variants play distinct and opposing roles in heart failure and ischemia / reperfusion injury. These opposing effects may need to be considered when developing CaMKII modulating drugs for clinical application application. .
- © 2012 by American Heart Association, Inc.