Adverse chromatin remodelling by SETD7 drives inflammation and diastolic dysfunction in obese heart failure with preserved ejection fraction

Abstract Background Obese heart failure with preserved ejection fraction (obHFpEF) is expected to rise considerably over the next decades, and associates with high mortality. Yet, the underlying mechanisms are poorly understood, and breakthrough therapies remain to be developed. Epigenetic modifications have recently emerged as key players in the pathophysiology of cardiovascular disease. Post-translational modification of histones by chromatin modifying enzymes (CME) play a pivotal role in regulating gene transcription. Purpose To investigate the role of chromatin remodeling in obHFpEF. Methods Unbiased gene expression profiling of CMEs (PCR array) was performed in left ventricular (LV) myocardial specimens from obHFpEF patients and age-matched control donors (n=10/group). Among myocardial CMEs, the methyltransferase SETD7 showed the highest variation in gene expression. Hence, we generated mice with cardiomyocyte-specific deletion of SETD7 (c-SETD7-/-) and control littermates (SETD7fl/fl) and subjected them to high fat diet feeding and L-NAME treatment for 15 weeks to induce obHFpEF. Echocardiography and Treadmill exhaustion test were performed. ChIP-Seq was employed investigate genome-wide SETD7/H3k4me1 distribution on target gene promoters. SETD7 gain- and loss-of-function experiments were performed in cultured neonatal rat ventricular myocytes (NRVMs) exposed to palmitic acid (200µM) for 48h. Selective inhibition of SETD7 by (R)-PFI-2 was performed in skinned cardiomyocytes isolated from left ventricular specimens of obHFpEF patients. Results SETD7 was the top-ranking transcript in myocardial specimens from obHFpEF patients as compared to controls. ChIP-Seq in CMs showed a strong redistribution of the SETD7-dpendent chromatin mark (H3k4me1) in HFpEF vs control CMs. Gene ontology enrichment analysis showed a strong occupancy of H3k4me1 on gene controlling inflammation (Fig. 1). SETD7 and H3k4me1 were upregulated in HFpEF vs. control mouse hearts, showed enrichment on NF-kB p65 promoter and were associated with IL-1β and IL-6 upregulation (Fig. 1). In HFpEF mice, cardiomyocyte-specific deletion of SETD7 protected against LV hypertrophy, diastolic dysfunction and lung congestion while improving exercise tolerance (Fig. 2). At the molecular level, SETD7 deletion blunted H3K4me1 enrichment on p65 promoter thus preventing the upregulation of inflammatory genes and myocardial apoptosis. In cultured CMs exposed to PA, SETD7 inhibition by (R)-PFI-2 prevented H3k4me1-driven p65 upregulation, whereas SETD7 overexpression mimicked HFpEF features. Moreover, knockdown of NF-kB p65 prevented IL-1β/IL-6 transcription in SETD7-overexpressing CMs. Of clinical relevance, (R)-PFI-2 reduced passive stiffness in skinned CMs isolated from obHFpEF patients. Conclusions we show that SETD7 activation contributes to the development of obHFpEF by fostering epigenomic rewiring and pro-inflammatory transcriptional programs.