Ketone-based metabolism and signalling in heart failure with preserved ejection fraction (HFpEF)

• Published in: Cardiovascular research 2024-05, Vol.120 (Supplement_1)
• Main Authors: Wang, R, Capone, F, Luo, L, L, L, Keller, D, Jung, S, Pauline, F, Mertins, P, Sotomayor-Flores, C, Bode, D, Grunert, N, Schiattarella, G
• Format: Article
• Language: English
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvae088.096

Funding Acknowledgements  Type of funding sources: Public grant(s) – EU funding. Main funding source(s): DZHK Deutsche Forschungsgemeinschaft (DFG-SFB_1470_A02) Cardiac metabolic remodelling in heart failure with preserved ejection fraction (HFpEF) underlies the pathogenesis of this syndrome. Yet, our understanding of metabolic alterations occurring in HFpEF hearts is still limited. Ketone bodies (KBs) – β-hydroxybutyrate (β-OHB) in particular – can become a major, alternative source of fuel for failing hearts. However, the biological relevance of KBs goes beyond their role as energy carrier. We used a ‘two-hit’ mouse model of HFpEF induced by high-fat-diet feeding and L-Name, aiming to evaluate metabolic alteration among various energy substrates (e.g., glucose, fatty acids), in particular the role of β-OHB in HFpEF hearts. Here, we showed that HFpEF heart exhibited impaired glucose oxidation and increased fatty acid oxidation. Impaired glucose oxidation was attributed to the reduced pyruvate dehydrogenase (PDH) activity and increased phospho-PDH expression via the activation of PDH kinase 4 (PDK4). The oxidation of β-OHB was reduced as a result of decreased β-OHB dehydrogenase (BDH1) and succinyl-coA-3-oxaloacid CoA transferase (SCOT) expression. Furthermore, we showed that β-OHB governs mitochondrial function and myocardial bioenergetics in HFpEF, acting as protein modifiers through β-hydroxybutyrylation (Kbhb) – a lysine-based post-translational modification (PTM). Immunoblot analysis for pan- β-hydroxybutyryllysine revealed a significant increase in Kbhb levels in the heart of ‘two-hit’ HFpEF mice compared to control mice. To identify the specific proteins and sites of Kbhb in the heart, Kbhb peptides from control and HFpEF mouse hearts were isolated by immunoaffinity enrichment using a pan-Kbhb antibody-conjugated beads. Volcano plot and gene ontology analysis showed that the most Kbhb-modified proteins in HFpEF hearts are mitochondrial enzymes. Glutamate oxaloacetate transaminase (GOT2) is one of the top hits, participating in the TCA cycle and malate-aspartate shuttle (MAS) in the mitochondria. We further demonstrated that GOT2 activity and MAS were enhacned in the mitochondrial of HFpEF hearts. To conclude, in the heart of ‘two-hit’ model of HFpEF, the oxidation of pyruvate was impaired resulting from decreased PDH activity. The oxidation of β-OHB was also reduced due to the down-regulated BDH1 activity. Instead of oxidation, Kbhb was highlighted