Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure
Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure
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DOI：
10.1161/circheartfailure.119.006573
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发表时间：
2020-06-01
影响因子：
9.7
通讯作者：
Dyck, Jason R. B.
中科院分区：
文献类型：
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作者：
Byrne, Nikole J.;Soni, Shubham;Dyck, Jason R. B.
背景：先前的研究表明，急性输注初级酮体-羟基丁酸酯对心力衰竭（HF）有有益作用。然而，循环酮的慢性升高是否有益仍是未知的。方法：为了慢性升高小鼠体内的循环酮，我们删除了骨骼肌中酮解酶、速率限制酶SCOT（琥珀酰辅酶a:3-酮酸辅酶a转移酶1；由Oxct1编码）的表达。他莫昔芬诱导的骨骼肌特异性Oxct1（Muscle-/-）敲除小鼠（n=32）和同窝对照小鼠（野生型；WT; n=35）采用主动脉横缩（TAC）手术诱导HF。结果：与WT小鼠相比，骨骼肌中SCOT的缺失导致敲除小鼠空腹循环β -羟基丁酸盐浓度升高（P=0.030）。TAC后5周，WT小鼠进展为HF，而在WT小鼠中观察到的空腹循环酮升高的敲除小鼠在很大程度上免受TAC诱导的影响（射血分数，P=0.011；二尖瓣E/A， P=0.012）。此外，TAC基因敲除小鼠无菌炎症和巨噬细胞浸润标志物的表达减弱，而TAC基因敲除小鼠无菌炎症和巨噬细胞浸润标志物的表达则升高。最后，在离体心脏中添加β -羟基丁酸与NLRP3（核苷酸结合结构域样受体蛋白3）炎性体激活降低有关，这在之前的研究中被证明在hf诱导的心脏炎症中起作用。结论：这些数据表明，循环酮的慢性升高可以防止HF的发展，这与β -羟基丁酸盐直接减少炎症的能力有关。酮类的这些有益作用与降低心脏NLRP3炎性体激活有关，表明酮类可能通过这一机制调节心脏炎症。
BACKGROUND: Previous studies have shown beneficial effects of acute infusion of the primary ketone body, beta-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 beta-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 beta-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 beta-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.