Aberrant Upregulation of Histamine N-Methyltransferase Exacerbates Pathological Cardiac Hypertrophy and Heart Failure via Disruption of SAM/Frizzled-2/ CaMKII Signaling Pathway [RNA-seq]
Metabolites produced during the development of pathological cardiac hypertrophy and heart failure can influence disease progression. Methyl donor S-adenosyl methionine (SAM) levels are decreased in the hypertrophic heart, but related mechanisms and effects remain unknown. Histamine N-methyltransferase (HNMT) uses SAM as a substrate to deactivate histamine into N-methylhistamine. Here, we prove that HNMT was upregulated in cardiac tissues from patients with heart failure and post-transverse aortic constriction (TAC) mice as well as phenylephrine (PE)-treated neonatal mouse cardiomyocytes (NMCMs). N-methylhistamine, downstream metabolite of HNMT, was elevated in urine samples from heart failure patients. In mice, cardiomyocyte-specific Hnmt deletion ameliorated pathological cardiac hypertrophy and heart failure caused by TAC or Angiotensin-II infusion. Pharmacological inhibition of HNMT with amodiaquine ameliorated TAC-induced cardiac dysfunction. In contrast, cardiomyocyte-specific Hnmt overexpression caused cardiac dysfunction. Mechanistically, HNMT decreased intracellular SAM levels and interacted with enhancer of zeste homolog2 (EZH2). This interaction blocked EZH2 function and downregulated H3K27me3 modification at the Frizzled-2 (Fzd2) promoter, which increased Fzd2 expression. FZD2 upregulation activated the calcium/calcium–calmodulin (CaM)-dependent protein kinase II (CaMKII) pathway, which mediated the pro-hypertrophic effects of HNMT. This study identified HNMT as a promising therapeutic target for treating pathological cardiac hypertrophy and heart failure. Overall design: RNA-seq data from neonatal mouse cardiomyocytes (NMCMs) transfected with control, HNMT-overexpressing, or HNMT-knockdown viruses, followed by phenylephrine (PE) treatment.