Background Energy starvation and the shift of energy substrate from fatty acids to glucose is the hallmark of metabolic remodeling during heart failure progression. However, ketone body metabolism in the failing heart has not been fully investigated.

Methods and Results Microarray data analysis and mitochondrial isobaric tags for relative and absolute quantification proteomics revealed that the expression of D-β-hydroxybutyrate dehydrogenase I (Bdh1), an enzyme that catalyzes the NAD⁺/NADH coupled interconversion of acetoacetate and β-hydroxybutyrate, was increased 2.5- and 2.8-fold, respectively, in the heart after transverse aortic constriction. In addition, ketone body oxidation was upregulated 2.2-fold in transverse aortic constriction hearts, as determined by the amount of ¹⁴CO₂ released from the metabolism of [1-¹⁴C] β-hydroxybutyrate in isolated perfused hearts. To investigate the significance of this augmented ketone body oxidation, we generated heart-specific Bdh1-overexpressing transgenic mice to recapitulate the observed increase in basal ketone body oxidation. Bdh1 transgenic mice showed a 1.7-fold increase in ketone body oxidation but did not exhibit any differences in other baseline characteristics. When subjected to transverse aortic constriction, Bdh1 transgenic mice were resistant to fibrosis, contractile dysfunction, and oxidative damage, as determined by the immunochemical detection of carbonylated proteins and histone acetylation. Upregulation of Bdh1 enhanced antioxidant enzyme expression. In our in vitro study, flow cytometry revealed that rotenone-induced reactive oxygen species production was decreased by adenovirus-mediated Bdh1 overexpression. Furthermore, hydrogen peroxide–induced apoptosis was attenuated by Bdh1 overexpression.

Conclusions We demonstrated that ketone body oxidation increased in failing hearts, and increased ketone body utilization decreased oxidative stress and protected against heart failure.

背景技术心力衰竭期间，能量匮乏和能量底物从脂肪酸到葡萄糖的转移是代谢重塑的标志。但是，尚未全面研究衰竭心脏中的酮体新陈代谢。

方法和结果微阵列数据分析和线粒体等压标记的相对和绝对定量蛋白质组学研究表明，D-β-羟基丁酸脱氢酶I（Bdh1）的表达，该酶催化NAD ⁺ / NADH偶联乙酰乙酸和β-羟基丁酸的相互转化，横断主动脉缩窄后，心脏的心电图分别增加了2.5倍和2.8倍。此外，在横断性主动脉缩窄的心脏中，酮体的氧化被上调了2.2倍，这取决于[1- ^14]代谢中释放出的¹⁴ CO ₂的量。C]离体灌注心脏中的β-羟基丁酸酯。为了研究这种增强的酮体氧化的重要性，我们生成了心脏特异性Bdh1过表达的转基因小鼠，以概括观察到的基础酮体氧化的增加。Bdh1转基因小鼠的酮体氧化显示增加了1.7倍，但其他基线特征没有任何差异。当受到横向主动脉收缩时，Bdh1转基因小鼠对纤维化，收缩功能障碍和氧化损伤具有抵抗力，这是通过对羰基化蛋白和组蛋白乙酰化的免疫化学检测确定的。Bdh1的上调增强了抗氧化酶的表达。在我们的体外研究中 流式细胞仪检测表明，腺病毒介导的Bdh1过表达降低了鱼藤酮诱导的活性氧的产生。此外，过氧化氢诱导的细胞凋亡因Bdh1过表达而减弱。

结论我们证明了衰竭心脏中酮体的氧化增加，而酮体利用率的增加降低了氧化应激并可以预防心力衰竭。