Abstract MP170: Increased Ga o Expression Regulated by NRSF Plays a Key Role in the Development of Heart Failure Through the Impairment of Ca 2+ Homeostasis

Abstract

Background: In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac gene program, which leads to pathological cardiac remodeling. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac gene program and maintains normal cardiac function, while pathological stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac function remains to be determined, however. Purpose: To elucidate molecular mechanisms by which NRSF maintains normal cardiac function. Methods and Results: Newly generated cardiac-specific NRSF knockout mice (NRSF-cKO) showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). Expression of Gnao1 gene encoding Gα o , a member of inhibitory G proteins, was commonly increased in ventricles of dnNRSF-Tg and NRSF-cKO. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gα o in dnNRSF-Tg and NRSF-cKO ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Conversely cardiac-specific GNAO1 overexpression was sufficient to show impaired cardiac function. Mechanistically, Gα o increases current density in surface sarcolemmal L-type Ca 2 + channel and then activates CaMKII without affecting protein kinase A activity, which finally leads to impaired Ca 2+ handling and systolic dysfunction. Furthermore, expression of Gα o is also increased in ventricles of transverse aortic constriction model mice and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gα o prevented the progression of cardiac dysfunction. Conclusions: Increased expression of Gα o , induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII and progresses heart failure by impairing Ca 2+ homeostasis. Gα o is a potential therapeutic target for heart failure.