Purpose

Ketone body oxidation yields more ATP per mole of consumed oxygen than glucose. However, whether an increased ketone body supply in hypoxic cardiomyocytes and ischemic hearts is protective or not remains elusive. The goal of this study is to determine the effect of β-hydroxybutyrate (β-OHB), the main constituent of ketone bodies, on cardiomyocytes under hypoxic conditions and the effects of ketogenic diet (KD) on cardiac function in a myocardial infarction (MI) mouse model.

Methods

Human peripheral blood collected from patients with acute myocardial infarction and healthy volunteers was used to detect the level of β-OHB. N-terminal proB-type natriuretic peptide (NT-proBNP) levels and left ventricular ejection fractions (LVEFs) were measured to study the relationship between plasma β-OHB and cardiac function. Adult mouse cardiomyocytes and MI mouse models fed a KD were used to research the effect of β-OHB on cardiac damage. qPCR, western blot analysis, and immunofluorescence were used to detect the interaction between β-OHB and glycolysis. Live/dead cell staining and imaging, lactate dehydrogenase, Cell Counting Kit-8 assays, echocardiography, and 2,3,5-triphenyltetrazolium chloride staining were performed to evaluate the cardiomyocyte death, cardiac function, and infarct sizes.

Results

β-OHB level was significantly higher in acute MI patients and MI mice. Treatment with β-OHB exacerbated cardiomyocyte death and decreased glucose absorption and glycolysis under hypoxic conditions. These effects were partially ameliorated by inhibiting hypoxia-inducible factor 1α (HIF-1α) degradation via roxadustat administration in hypoxia-stimulated cardiomyocytes. Furthermore, β-OHB metabolisms were obscured in cardiomyocytes under hypoxic conditions. Additionally, MI mice fed a KD exhibited exacerbated cardiac dysfunction compared with control chow diet (CD)-fed MI mice.

Conclusion

Elevated β-OHB levels may be maladaptive to the heart under hypoxic/ischemic conditions. Administration of roxadustat can partially reverse these harmful effects by stabilizing HIF-1α and inducing a metabolic shift toward glycolysis for energy production.

中文翻译：

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β-羟基丁酸通过抑制心肌细胞中 HIF-1α 依赖性糖酵解而加剧缺氧损伤——火上浇油？

目的

酮体氧化每摩尔消耗的氧气产生比葡萄糖更多的 ATP。然而，缺氧心肌细胞和缺血心脏中酮体供应增加是否具有保护作用仍不清楚。本研究的目的是确定酮体的主要成分β-羟基丁酸（β-OHB）在缺氧条件下对心肌细胞的影响，以及生酮饮食（KD）对心肌梗死（MI）心脏功能的影响。 ）鼠标模型。

方法

采集急性心肌梗死患者和健康志愿者外周血，检测β-OHB水平。测量 N 端 B 型利钠肽原 (NT-proBNP) 水平和左心室射血分数 (LVEF)，以研究血浆 β-OHB 与心功能之间的关系。使用 KD 喂养的成年小鼠心肌细胞和 MI 小鼠模型来研究 β-OHB 对心脏损伤的影响。qPCR、蛋白质印迹分析和免疫荧光用于检测 β-OHB 与糖酵解之间的相互作用。进行活/死细胞染色和成像、乳酸脱氢酶、细胞计数试剂盒-8测定、超声心动图和2,3,5-三苯基氯化四唑染色来评估心肌细胞死亡、心脏功能和梗死面积。

结果

急性心肌梗死患者和心肌梗死小鼠的β-OHB水平显着升高。β-OHB 治疗加剧了心肌细胞死亡，并减少了缺氧条件下的葡萄糖吸收和糖酵解。通过在缺氧刺激的心肌细胞中施用罗沙司他来抑制缺氧诱导因子 1α (HIF-1α) 降解，可以部分改善这些效应。此外，缺氧条件下心肌细胞中的 β-OHB 代谢变得模糊。此外，与对照饲料 (CD) 喂养的 MI 小鼠相比，饲喂 KD 的 MI 小鼠表现出更严重的心功能障碍。

结论

β-OHB 水平升高可能会导致心脏在缺氧/缺血条件下适应不良。给予 roxadustat 可以通过稳定 HIF-1α 并诱导代谢转向糖酵解以产生能量，从而部分逆转这些有害影响。