Nikole J Byrne1,2, Shubham Soni1,2,3, Shingo Takahara1,4, Mourad Ferdaoussi1, Rami Al Batran1,3,5, Ahmed M Darwesh5, Jody L Levasseur1, Donna Beker1, Dyonne Y Vos1, Mya A Schmidt1, Abrar S Alam1, Zaid H Maayah1,2, Jonathan D Schertzer6, John M Seubert1,7,5, John R Ussher1,3,5, Jason R B Dyck1,2,3. 1. Cardiovascular Research Centre (N.J.B., S.S., S.T., M.F., R.A.B., J.L.L., D.B., D.Y.V., M.A.S., A.S.A., Z.H.M., J.M.S., J.R.U., J.R.B.D.), University of Alberta, Edmonton, Canada. 2. Department of Pediatrics (N.J.B., S.S., Z.H.M., J.R.B.D.), University of Alberta, Edmonton, Canada. 3. Alberta Diabetes Institute (S.S., R.A.B., J.R.U., J.R.B.D.), University of Alberta, Edmonton, Canada. 4. Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.T.). 5. Faculty of Medicine and Dentistry, and Faculty of Pharmacy and Pharmaceutical Sciences (R.A.B., A.M.D., J.M.S., J.R.U.), University of Alberta, Edmonton, Canada. 6. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada (J.D.S.). 7. Department of Pharmacology (J.M.S), University of Alberta, Edmonton, Canada.
Abstract
BACKGROUND: Previous studies have shown beneficial effects of acute infusion of the primary ketone body, β-hydroxybutyrate, in heart failure (HF). However, whether chronic elevations in circulating ketones are beneficial remains unknown. METHODS: To chronically elevate circulating ketones in mice, we deleted the expression of the ketolytic, rate-limiting-enzyme, SCOT (succinyl-CoA:3-ketoacid-CoA transferase 1; encoded by Oxct1), in skeletal muscle. Tamoxifen-inducible skeletal muscle-specific Oxct1Muscle-/- knockout (n=32) mice and littermate controls (wild type; WT; n=35) were subjected to transverse aortic constriction (TAC) surgery to induce HF. RESULTS: Deletion of SCOT in skeletal, but not cardiac muscle resulted in elevated concentrations of fasted circulating β-hydroxybutyrate in knockout mice compared with WT mice (P=0.030). Five weeks following TAC, WT mice progressed to HF, whereas knockout mice with elevated fasting circulating ketones were largely protected from the TAC-induced effects observed in WT mice (ejection fraction, P=0.011; mitral E/A, P=0.012). Furthermore, knockout mice with TAC had attenuated expression of markers of sterile inflammation and macrophage infiltration, which were otherwise elevated in WT mice subjected to TAC. Lastly, addition of β-hydroxybutyrate to isolated hearts was associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3)-inflammasome activation, which has been previously shown to play a role in contributing to HF-induced cardiac inflammation. CONCLUSIONS: These data show that chronic elevation of circulating ketones protects against the development of HF that is associated with the ability of β-hydroxybutyrate to directly reduce inflammation. These beneficial effects of ketones were associated with reduced cardiac NLRP3 inflammasome activation, suggesting that ketones may modulate cardiac inflammation via this mechanism.
BACKGROUND: Previous studies have shown beneficial effects of acute infusion of the primary ketone body, β-hydroxybutyrate, in heart failure (HF). However, whether chronic elevations in circulating ketones are beneficial remains unknown. METHODS: To chronically elevate circulating ketones in mice, we deleted the expression of the ketolytic, rate-limiting-enzyme, SCOT (succinyl-CoA:3-ketoacid-CoA transferase 1; encoded by Oxct1), in skeletal muscle. Tamoxifen-inducible skeletal muscle-specific Oxct1Muscle-/- knockout (n=32) mice and littermate controls (wild type; WT; n=35) were subjected to transverse aortic constriction (TAC) surgery to induce HF. RESULTS: Deletion of SCOT in skeletal, but not cardiac muscle resulted in elevated concentrations of fasted circulating β-hydroxybutyrate in knockout mice compared with WT mice (P=0.030). Five weeks following TAC, WT mice progressed to HF, whereas knockout mice with elevated fasting circulating ketones were largely protected from the TAC-induced effects observed in WT mice (ejection fraction, P=0.011; mitral E/A, P=0.012). Furthermore, knockout mice with TAC had attenuated expression of markers of sterile inflammation and macrophage infiltration, which were otherwise elevated in WT mice subjected to TAC. Lastly, addition of β-hydroxybutyrate to isolated hearts was associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3)-inflammasome activation, which has been previously shown to play a role in contributing to HF-induced cardiac inflammation. CONCLUSIONS: These data show that chronic elevation of circulating ketones protects against the development of HF that is associated with the ability of β-hydroxybutyrate to directly reduce inflammation. These beneficial effects of ketones were associated with reduced cardiac NLRP3 inflammasome activation, suggesting that ketones may modulate cardiac inflammation via this mechanism.
Authors: Shingo Takahara; Shubham Soni; Kiran Phaterpekar; Ty T Kim; Zaid H Maayah; Jody L Levasseur; Heidi L Silver; Darren H Freed; Mourad Ferdaoussi; Jason R B Dyck Journal: ESC Heart Fail Date: 2021-10-06
Authors: Dimitrios A Vrachatis; Konstantinos A Papathanasiou; Konstantinos E Iliodromitis; Sotiria G Giotaki; Charalampos Kossyvakis; Konstantinos Raisakis; Andreas Kaoukis; Vaia Lambadiari; Dimitrios Avramides; Bernhard Reimers; Giulio G Stefanini; Michael Cleman; Georgios Giannopoulos; Alexandra Lansky; Spyridon G Deftereos Journal: Drugs Date: 2021-07-23 Impact factor: 9.546