title: β-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes.
abstract: Recent studies have shown that the ketone body β-hydroxybutyrate (βOHB) acts not only as a carrier of energy but also as a signaling molecule that has a role in diverse cellular functions. Circulating levels of ketone bodies have been previously reported to be increased in patients with congestive heart failure (HF). In this study, we investigated regulatory mechanism and pathophysiological role of βOHB in HF. First, we revealed that βOHB level was elevated in failing hearts, but not in blood, using pressure-overloaded mice. We also measured cellular βOHB levels in both cardiomyocytes and non-cardiomyocytes stimulated with or without H2O2 and revealed that increased myocardial βOHB was derived from cardiomyocytes but not non-cardiomyocytes under pathological states. Next, we sought to elucidate the mechanisms of myocardial βOHB elevation and its implication under pathological states. The gene and protein expression levels of CoA transferase (SCOT), a key enzyme involved in ketone body oxidation, was decreased in failing hearts. In cardiomyocytes, H2O2 stimulation caused βOHB accumulation concomitantly with SCOT downregulation, implying that the accumulation of myocardial βOHB occurs because of the decline in its utilization. Finally, we checked the effects of βOHB on cardiomyocytes under oxidative stress. We found that βOHB induced FOXO3a, an oxidative stress resistance gene, and its target enzyme, SOD2 and catalase. Consequently, βOHB attenuated reactive oxygen species production and alleviated apoptosis induced by oxidative stress. It has been reported that hyperadrenergic state in HF boost lipolysis and result in elevation of circulating free fatty acids, which can lead hepatic ketogenesis for energy metabolism alteration. The present findings suggest that the accumulation of βOHB also occurs as a compensatory response against oxidative stress in failing hearts.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Nagao
authors.affiliation: Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, Japan. Electronic address: rtoh@med.kobe-u.ac.jp.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Toh
authors.affiliation: Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Irino
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan.
authors.forename: Takeshige
authors.initials: T
authors.lastname: Mori
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hara
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Honjo
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan.
authors.forename: Seimi
authors.initials: S
authors.lastname: Satomi-Kobayashi
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shinke
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University, Graduate School of Medicine, Japan; Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hirata
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D015256:Coenzyme A-Transferases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress; D051381:Rats
chemical_list: D006861:Hydrogen Peroxide; D015256:Coenzyme A-Transferases; D020155:3-Hydroxybutyric Acid
keywords: Forkhead box O3a (FOXO3a); Heart failure; Oxidative stress; Succinyl-CoA:3-oxoacid-CoA transferase (SCOT); β-hydroxybutyrate