The histone methyltransferase SETD2 promotes lipotoxic injury in cardiometabolic heart failure with preserved ejection fraction

Background Cardiometabolic heart failure with preserved ejection fraction (cHFpEF) is a complex multisystemic syndrome characterized by high morbidity and mortality. Epigenetic modifications - defined as plastic changes of chromatin that do not alter DNA sequence - have recently emerged as key players in the pathophysiology of cardiovascular disease. Among epigenetic signals, histone 3 trimethylation at lysine 36 (H3k36me3) - a chromatin signature induced by the histone methyltransferase SETD2 - correlates with changes in gene expression in human failing hearts; however, its role remains poorly understood. Purpose This study investigates the role of SETD2 in cHFpEF. Methods Chromatin immunoprecipitation sequencing (ChIPseq) and RNAseq were employed to investigate H3k36me3-related transcriptional regulation. Mice with cardiomyocyte-specific deletion of SETD2 (c-SETD2-/-) were generated and subjected to high fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Cardiac function and exercise tolerance were assessed by echocardiography and Treadmill exhaustion test. A selective pharmacological inhibitor of SETD2, EZM0414, was also tested in cHFpEF mice. Mechanistic experiments were performed in cultured cardiomyocytes (CMs) exposed to palmitic acid (PA). SETD2 signaling and the effects of EZM0414 were also investigated in CMs from cHFpEF patients and control donors. Results SETD2 was upregulated in cHFpEF mouse hearts and its chromatin mark H3k36me3 was involved in lipid metabolism and highly enriched on the promoter of sterol regulatory element-binding transcription factor 1 (Srebf1) gene, encoding for the SREBP1 protein. SETD2 activation in cHFpEF led to SREBP1 upregulation, triglyceride accumulation and lipotoxic damage (Figure 1). Of note, cardiomyocyte-specific deletion of SETD2 in mice prevented HFpEF-related hypertrophy, diastolic dysfunction and lung congestion while improving exercise tolerance (Figure 2). SETD2 deletion blunted H3K36me3 enrichment on Srebf1 promoter thus leading to a marked rewiring of the cardiac lipidome and restoration of autophagic flux. In vivo treatment with the SETD2 inhibitor EZM0414 recapitulated the effects of SETD2 deletion. Silencing of SETD2 in PA-treated CMs prevented SREBP1 upregulation, whereas SETD2 overexpression mirrored lipotoxic damage. Finally, SETD2 was upregulated in LV specimens from cHFpEF patients while EZM0414 attenuated CM stiffness. Conclusions We show that SETD2 drives lipotoxic damage in cardiometabolic HFpEF via transcriptional regulation of SREBP1. Our translational study unveils a novel epigenetic mechanism and a druggable target to prevent lipotoxic injury, defective autophagy and cardiomyocyte dysfunction in cHFpEF.