Abstract 075: Ketone Bodies Rescue Mitochondrial Dysfunction And Improve Maladaptive Epigenetic Remodeling In Heart Failure

Abstract

CATEGORY: Genetics, Epigenetics and Epidemiology Ketone Bodies Rescue Mitochondrial Dysfunction and Improve Maladaptive Epigenetic Remodeling in Heart Failure Fahimeh Varzideh 1 , Stanislovas S. Jankauskas 1 , Urna Kansakar 1 , Simone Sidoli 1 , Jessica Gambardella 1 , Gaetano Santulli 1 1 : Albert Einstein College of Medicine, 10461, New York, NY, USA Background: The exact molecular processes leading to the progression of post-ischemic heart failure (HF) are not fully understood. Methods: we carried out a comprehensive and coordinated set of in vivo and in vitro experiments using human cardiac specimens from patients with post-ischemic HF and healthy controls, a mouse model of HF, and mechanistic studies in vitro . Results: We identified, for the first time to our knowledge, a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and one methylation of lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF, murine HF, and in vitro models. To translate our findings in vivo , we used an established murine model of HF induced by myocardial infarction, obtained by permanent ligation of the left anterior descending coronary artery. After surgery, the mice were fed standard diet or diet supplemented with β-hydroxybutyrate (BHB), the most abundant ketone body in humans, for one month. Mechanistically, we demonstrate that the histone modification H3_K27me2K36me1 mediates the ischemia-induced transcriptional repression of PPARG Coactivator 1α (PGC1α), a master regulator of mitochondrial function and biogenesis. Strikingly, both the augmented H3_K27me2K36me1 and the PGC1α-mediated mitochondrial dysfunction were significantly attenuated by the treatment with BHB, revealing an unprecedented molecular pathway coupling metabolism to gene expression. The increased circulating levels of ketone bodies observed in HF patients treated with SGLT2 inhibitors further supports our preclinical results. Conclusion: Collectively, our findings establish maladaptive chromatin remodeling as a key mechanism in post-ischemic heart injury, functionally modulated by ketone bodies.