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SHR Neuro Cancer Cardio Lipid Metab Microb

Byrne, NJ; Soni, S; Takahara, S; Ferdaoussi, M; Al, Batran, R; Darwesh, AM; Levasseur, JL; Beker, D; Vos, DY; Schmidt, MA; Alam, AS; Maayah, ZH; Schertzer, JD; Seubert, JM; Ussher, JR; Dyck, JRB.
Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure.
Circ Heart Fail. 2020; 13(6): e006573 Doi: 10.1161/CIRCHEARTFAILURE.119.006573
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Leading authors Med Uni Graz: Byrne Nikole
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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 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.
Find related publications in this database (using NLM MeSH Indexing): 3-Hydroxybutyric Acid - blood; Animals - administration & dosage; Coenzyme A-Transferases - deficiency, genetics; Disease Models, Animal - administration & dosage; Fibrosis - administration & dosage; Heart Failure - blood, enzymology, physiopathology, prevention & control; Hypertrophy, Left Ventricular - blood, physiopathology, prevention & control; Inflammasomes - metabolism; Isolated Heart Preparation - administration & dosage; Male - administration & dosage; Mice, Knockout - administration & dosage; Myocarditis - blood, enzymology, physiopathology, prevention & control; Myocardium - enzymology, pathology; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Up-Regulation - administration & dosage; Ventricular Dysfunction, Left - blood, physiopathology, prevention & control; Ventricular Function, Left - administration & dosage; Ventricular Remodeling - administration & dosage
Find related publications in this database (Keywords): cytokines; heart; heart failure; inflammasome; inflammation; ketone bodies