Authors: Stanislovas S Jankauskas, Jessica Gambardella, Fahimeh Varzideh, Urna Kansakar, Pasquale Mone, Simone Sidoli, Gaetano Santulli
Published: 2022-11-14
DOI: 10.1161/res.131.suppl_1.p2004
Source: Full article
Mitochondrial dysfunction plays a crucial role in the pathogenesis of heart failure with reduced ejection fraction (HFrEF). The ketone body beta-hydroxybutyrate (BHB) was suggested to improve mitochondrial function. However, the mechanisms are not fully understood and no studies investigated BHB effect on mitochondrial dysfunction and cardiac insufficiency in HFrEF. HFrEF was modeled in mice by permanent occlusion of the left anterior descending coronary artery causing myocardial infarction (MI). After surgery, mice were fed with BHB diet or standard chow. Sham operated mice on standard chow served as a control. BHB diet increased BHB plasma level 2.75 times compared to mice on standard chow. Four weeks after MI, BHB diet significantly improved cardiac remodeling, evident by decreased myocardial fibrosis, higher ejection fraction, lower left ventricular diastolic volume, and robust downregulation of atrial natriuretic peptide. Strikingly, survival rate was 25% for mice on normal chow and 60% for mice on BHB-diet. In primary isolated cardiomyocytes, we observed that BHB diet also shortened sarcomere time to peak contraction. Basal and maximal cardiac mitochondria respiration was reduced 4 weeks after MI alongside with downregulation of the master-regulator of mitochondrial biogenesis, PGC1α. BHB-diet ameliorated MI-induced downregulation of PGC1α, restored mitochondrial respiration, and prevented mitochondrial calcium overload. By analyzing cardiac human specimens, we discovered that Histone 3 lysin 26 dimethylation and lysin 36 methylation (H3K26me2/H3K36me) were significantly higher in human heart samples from patients with HFrEF compared to healthy controls; similar findings were observed in MI hearts compared to sham. BHB diet downregulated H3K26me2/H3K36me in murine hearts. Chromatin immunoprecipitation of H3K26me2/H3K36me revealed a PGC1α promoter enrichment. H3K26me2/H3K36me was also upregulated after ischemia