Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival: part 2.

ABSTRACT: Cardiac hypertrophy is a potentially fatal disease characterized by increased cardiomyocyte size, and maladaptive transcriptional remodeling that leads to arrythmias and contractile failure. Transgenic mice constitutively expressing high levels of calcineurin develop extreme heart hypertrophy and generally die within a few weeks of birth. Here, we characterize the transcriptional and epigenetic pathways that are aberrant in this mouse model and establish a pharmacological approach to treating cardiac hypertrophy based on our observation that a subset of histone demethylases of the Jumonji KDM family that act on H3K4me3 or H3K9me3 are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. Inhibition of Jumonji demethylases in vivo results in lower histone demethylase enzymatic activity in the heart without toxicity, and leads to partial reduction of heart size, to the reversal of maladaptive transcriptional programs, to improved heart function, and to prolongation of survival. Mechanistically, MEF2, KDM4A and KDM3A target genes are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases and NFAT remains largely cytoplasmic. Similar transcriptional reversal of disease genes is seen in a second disease model based on cardiac mechanical overload, suggesting the generality of this approach. Our findings establish the use of pharmacological inhibitors of Jumonji enzymes as potential therapeutics for the treatment of cardiac hypertrophy across disease models and provides evidence of the reversal of maladaptive transcriptional reprogramming in the heart leading to partial restoration of cardiac function.

ORGANISM(S): Mus musculus

PROVIDER: GSE169078 | GEO | 2022/02/08

REPOSITORIES: GEO