Abstract 457: Ca2+/calmodulin Dependent Kinase II Exacerbates Heart Failure Progression Through Activation of Class I Histone Deacetylases

Abstract

Background: Persistent cardiac Ca2+/calmodulin dependent Kinase II (CaMKII) activation in patients receiving standard heart failure therapies, appears to play an essential role in heart failure development. The molecular mechanisms of CaMKII induced heart failure progression remains incompletely understood and new mechanism based therapeutic strategies are warranted. Histone deacetylases (HDACs) are critical for transcriptional genes reprogramming leading to adverse ventricular remodeling. Class I HDACs, including HDAC 1, HDAC2 and HDAC3, promote pathological cardiac hypertrophy, whereas class IIa HDACs suppress cardiac hypertrophy. It is known that CaMKII deactivates class IIa HDACs to enhance cardiac hypertrophy, however, it is unknown whether CaMKII also regulates class I HDACs in heart failure development. Results: We found that CaMKII directly phosphorylates recombinant HDAC1 protein and increases its deacetylase activity by three-fold. HDAC1 activity is also increased in cardiac specific CaMKII over-expressing transgenic mice (CaMKII-TG). Mass spectrometry reveals HDAC1 is a CaMKII substrate. Beyond direct phosphorylation, CaMKII also increases HDAC1 expression. In cultured neonatal rat cardiac myocytes, overexpression of CaMKII markedly increases HDAC1 expression, and this CaMKII induced HDAC1 upregulation is mediated through JNK pathway, as JNK inhibitor SP600125 blunts this upregulation. HDAC1 expression is significantly increased in vivo, in CaMKII-TG mice. Consistently, the expression of HDAC1 is increased in failing hearts from wild type mice after myocardial infarction surgery, and this upregulation is attenuated in transgenic mice with myocardial expression of AC3-I, a CaMKII inhibitory peptide. Importantly, an HDAC1 specific inhibitor Quisinostat prevents or improves CaMKII overexpression induced cardiac hypertrophy and heart failure progression in vitro and in vivo. In addition, CaMKII also increases deacetylase activity and expression of other Class I HDACs, HDAC2 and HDAC3. Conclusion: CaMKII activates class I HDACs in heart failure, which may be a central mechanism for heart failure progression.