Abstract 471: Paradigm Shift to Epigenetic Memory for the Pathological Understanding of Chronic Heart Failure
Background- Epigenetic modification becomes a popular regulatory mechanism of gene expression in development or tumor progression. However its role in cardiovascular diseases has not been elucidated. Since reactivation of cardiac fetal gene expression in chronic heart failure (CHF) is more remarkable than that expected by the increased transcriptional factors, the concept of epigenetic modification may be required for the explanation of such a phenomenon. We tested this idea.
Methods- To test the epigenetic potency in cardiomyocytes, we focused on the expression of both BNP and ANP genes. As epigenetic markers, nucleic chromatin structure by electron microscopy and the entire-regional histone modifications were evaluated using our newly developed in vivo chromatin immunoprecipitation (ChIP) assay.
Results- In the developmental stage of hearts, we observed a parallel movement of fetal gene expression and epigenetic markers. On the other hand, in the short time stimuli of GPCR agonists in murine cardiomyocytes, fetal gene expression was controlled only by the amount of transcription factors, Gata4 and Nkx2.5, but epigenetic maker was not altered. In contrast, in in vivo murine model of CHF both Gata4 and Nkx2.5 depressed despite elevated expression of both BNP and ANP. Nucleic chromatin structure in failing cardiomyocytes was changed to less condensed forms and increased accumulation of both histone H3K9-acetylation and H3K4-trimethylation was observed across these gene loci. Also in human failing heart, similar changes of nucleic chromatin structure were observed as that in murine CHF model and interestingly these changes was reversed when the heart function was recovered along with proper treatment.
Conclusions- We for the first time clarified that both BNP and ANP reactivation mechanisms in chronic heart failure link to the alteration of histone modification by the in vivo ChIP method. Different from acute stimuli, this change was coincided with nucleic chromatin structure and was explicable of paradoxical depression of transcription factors, suggesting epigenetic potency. Epigenetic mechanism may play a pivotal role in the nuclear memory-mediating failing myocardium, raising the hope for a novel pathological understanding for human CHF.