Palmitic acid promotes hypertrophic memory in cardiomyocytes via KDM5A/H3K4me3

BACKGROUND AND AIMS: Palmitic acid (PA), the most abundant saturated fatty acid (SFA), is positively associated with heart failure (HF) risk. However, its role and mechanism underlying HF remain unclear. This study aimed to investigate the effects of a PA-enriched diet and potential therapeutic targets in HF. METHODS: The association between plasma SFAs and HF was investigated in a cohort of 232 592 UK Biobank participants. Mice were randomly categorized into three groups, where they were fed a PA-enriched, olive oil-enriched, or control diet for 4 weeks, followed by a 4-week dietary adaptation period on the control diet. A pressure overload model was established by transverse aortic constriction in these mice and cardiac-specific lysine demethylase 5A (Kdm5A)-knockout mice. RESULTS: The UK Biobank database revealed an association between high plasma SFA levels and increased HF risk. Our in vitro and in vivo results demonstrated that short-term PA treatment promoted cardiac hypertrophy and HF without further exposure to high levels of PA, indicating a pro-hypertrophic memory in cardiomyocytes. Mechanistically, PA promoted palmitoylation-driven KDM5A degradation via the ubiquitination pathway, thereby up-regulating histone 3 lysine 4 tri-methylation (H3K4me3). KDM5A/H3K4me3 promoted a pro-hypertrophic memory in cardiomyocytes, thus causing cardiac hypertrophy via a monocarboxylate transporter 4 (MCT4)-induced metabolic imbalance. Furthermore, KDM5A agonist D18 ameliorated this PA-mediated cardiac hypertrophy and HF. CONCLUSIONS: A PA-enriched diet promotes pro-hypertrophic memory in cardiomyocytes, cardiac hypertrophy, and HF via KDM5A/H3K4me3/MCT4. The application of D18 may represent a promising therapeutic approach for PA-mediated cardiac hypertrophy and HF.