BackgroundAlterations of energetic metabolism are suggested to be an important contributor to pressure overload (PO)‐induced heart failure. Our previous study reveals that knockout of endothelial Sirtuin 3 (SIRT3) alters glycolysis and impairs diastolic function. We hypothesize that endothelial SIRT3 regulates glucose utilization of cardiomyocytes and sensitizes PO‐induced heart failure.Methods and ResultsSIRT3 endothelial cell knockout mice and their control SIRT3 LoxP mice were subjected to PO by transverse aortic constriction for 7 weeks. The ratio of heart weight to tibia length was increased in both strains of mice, in which SIRT3 endothelial cell knockout mice+transverse aortic constriction exhibited more severe cardiac hypertrophy. Coronary blood flow and systolic function were significantly decreased in SIRT3 endothelial cell knockout mice+transverse aortic constriction compared with SIRT3 LoxP mice+transverse aortic constriction, as evidenced by lower systolic/diastolic ratio, ejection fraction, and fractional shortening. PO‐induced upregulation of apelin and glucose transporter 4 were significantly reduced in the hearts of SIRT3 endothelial cell knockout mice. In vitro, levels of hypoxia‐inducible factor‐1α and glucose transporter 1 and glucose uptake were significantly reduced in SIRT3 knockout endothelial cells. Furthermore, hypoxia‐induced apelin expression was abolished together with reduced apelin‐mediated glucose uptake in SIRT3 knockout endothelial cells. Exposure of cardiomyocyte with apelin increased expression of glucose transporter 1 and glucose transporter 4. This was accompanied by a significant increase in glycolysis. Supplement of apelin in SIRT3 knockout hypoxic endothelial cell media increased glycolysis in the cardiomyocytes.ConclusionsKnockout of SIRT3 disrupts glucose transport from endothelial cells to cardiomyocytes, reduces cardiomyocyte glucose utilization via apelin in a paracrine manner, and sensitizes PO‐induced heart failure. Endothelial SIRT3 may regulate cardiomyocyte glucose availability and govern the function of the heart.

中文翻译：

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内皮Sirtuin 3决定葡萄糖向心肌细胞的转运，并引起压力超负荷引起的心力衰竭。

背景高能代谢的改变被认为是压力超负荷的重要因素（PO）引起的心力衰竭。我们之前的研究表明，内皮Sirtuin 3（SIRT3）改变糖酵解并损害舒张功能。我们假设内皮SIRT3调节心肌细胞的葡萄糖利用并敏化 PO诱发的心力衰竭方法与结果SIRT3只内皮细胞敲除小鼠及其对照 SIRT对3只LoxP小鼠进行了 PO经主动脉缩窄术持续7周。两种小鼠的心重与胫骨长度之比均增加，其中SIRT3只内皮细胞敲除小鼠+横向主动脉缩窄表现出更严重的心脏肥大。冠状动脉血流和收缩功能明显降低。SIRT3只内皮细胞敲除小鼠+主动脉横向狭窄 SIRT3只LoxP小鼠+主动脉缩窄，表现为收缩压/舒张压降低，射血分数降低和分数缩短。 PO导致心脏中apelin和葡萄糖转运蛋白4的上调明显减少 SIRT3只内皮细胞敲除小鼠。在体外，低氧诱导因子-1α和葡萄糖转运蛋白1的水平以及葡萄糖的摄取显着降低。SIRT3个敲除的内皮细胞。此外，缺氧诱导的apelin表达被消除，同时减少了apelin介导的葡萄糖摄取。SIRT3个敲除的内皮细胞。用apelin暴露心肌细胞会增加葡萄糖转运蛋白1和葡萄糖转运蛋白4的表达。这伴随着糖酵解的显着增加。中的apelin的补充SIRT3种敲除的低氧内皮细胞介质增加了心肌细胞的糖酵解。 SIRT3破坏葡萄糖从内皮细胞向心肌细胞的运输，通过旁分泌方式通过apelin降低心肌细胞对葡萄糖的利用，并致敏 PO诱发的心力衰竭。内皮细胞SIRT3可能调节心肌细胞葡萄糖的可用性并控制心脏的功能。