Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure.

Autor:	Byrne NJ; 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.; Department of Pediatrics (N.J.B., S.S., Z.H.M., J.R.B.D.), University of Alberta, Edmonton, Canada., Soni S; 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.; Department of Pediatrics (N.J.B., S.S., Z.H.M., J.R.B.D.), University of Alberta, Edmonton, Canada.; Alberta Diabetes Institute (S.S., R.A.B., J.R.U., J.R.B.D.), University of Alberta, Edmonton, Canada., Takahara S; 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.; Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.T.)., Ferdaoussi M; 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., Al Batran R; 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.; Alberta Diabetes Institute (S.S., R.A.B., J.R.U., J.R.B.D.), University of Alberta, Edmonton, Canada.; 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., Darwesh AM; 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., Levasseur JL; 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., Beker D; 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., Vos DY; 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., Schmidt MA; 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., Alam AS; 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., Maayah ZH; 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.; Department of Pediatrics (N.J.B., S.S., Z.H.M., J.R.B.D.), University of Alberta, Edmonton, Canada., Schertzer JD; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada (J.D.S.)., Seubert JM; 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.; Department of Pharmacology (J.M.S), University of Alberta, Edmonton, Canada.; 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., Ussher JR; 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.; Alberta Diabetes Institute (S.S., R.A.B., J.R.U., J.R.B.D.), University of Alberta, Edmonton, Canada.; 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., Dyck JRB; 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.; Department of Pediatrics (N.J.B., S.S., Z.H.M., J.R.B.D.), University of Alberta, Edmonton, Canada.; Alberta Diabetes Institute (S.S., R.A.B., J.R.U., J.R.B.D.), University of Alberta, Edmonton, Canada.
Jazyk:	angličtina
Zdroj:	Circulation. Heart failure [Circ Heart Fail] 2020 Jun; Vol. 13 (6), pp. e006573. Date of Electronic Publication: 2020 Jun 04.
DOI:	10.1161/CIRCHEARTFAILURE.119.006573
Abstrakt:	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 Oxct1 Muscle- / - 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.
Databáze:	MEDLINE
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