Molecular basis of therapeutic effects of β-hydroxybutyrate on cardiac hypertrophy

Abstract

This study was aimed to explore the molecular basis underlying the therapeutic effects of β-hydroxybutyrate in cardiac hypertrophy. We established a model of cardiomyocyte hypertrophy in H9c2 cells induced by angiotensin II (AngII). The anti-hypertrophic effects of β-hydroxybutyrate were evaluated by assessing cell apoptosis and expression levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and nuclear factor of activated T-cells 1 (NFATc1). The miRNA-mRNA network and associated functional analyses were performed based on miRNA sequencing data. Expression levels of six miRNAs involved in the miRNA-mRNA network were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Eight mM β-hydroxybutyrate significantly attenuated AngIIinduced cell apoptosis and significantly decreased the AngII-induced upregulation of ANP (p < 0.01), BNP (p < 0.01), and NFATc1 (p < 0.01). Based on the miRNA sequencing data, 1327 miRNA-mRNA pairs were screened, including miR-672-3p, miR-760-5p, miR-6325, miR-3583-3p, miR-3065-3p, and miR-3541. Functional analysis revealed that target genes were significantly enriched in four KEGG pathways, including the Wnt signaling pathway, tumor necrosis factor (TNF) signaling pathway, adherens junction, and Hippo signaling pathway. These genes were significantly enriched in eight biological processes, including protein deneddylation, amino acid transmembrane transport, and amino acid transport. Following treatment with β-hydroxybutyrate, the expression levels of miR-672-3p, miR760-5p, miR-3583-3p, miR-3065-3p, and miR-3541 were significantly upregulated, and miR-6325 was significantly downregulated when compared with AngII treatment. Our data confirmed the protective role of β-hydroxybutyrate on cardiac hypertrophy, providing insights into observed therapeutic effects.