BACKGROUND Metabolic remodeling and mitochondrial dysfunction are hallmarks of heart failure with reduced ejection fraction. However, their role in the pathogenesis of HF with preserved ejection fraction (HFpEF) is poorly understood. METHODS In a mouse model of HFpEF, induced by high-fat diet and Nω-nitrol-arginine methyl ester, cardiac energetics was measured by 31P nuclear magnetic resonance (NMR) spectroscopy and substrate oxidation profile was assessed by 13C-isotopmer analysis. Mitochondrial functions were assessed in the heart tissue and human induced pluripotent stem cell-derived cardiomyocytes. RESULTS HFpEF hearts presented a lower phosphocreatine content and a reduced phosphocreatine/ATP ratio, similar to that in heart failure with reduced ejection fraction. Decreased respiratory function and increased reactive oxygen species production were observed in mitochondria isolated from HFpEF hearts suggesting mitochondrial dysfunction. Cardiac substrate oxidation profile showed a high dependency on fatty acid oxidation in HFpEF hearts, which is the opposite of heart failure with reduced ejection fraction but similar to that in high-fat diet hearts. However, phosphocreatine/ATP ratio and mitochondrial function were sustained in the high-fat diet hearts. We found that mitophagy was activated in the high-fat diet heart but not in HFpEF hearts despite similar extent of obesity suggesting that mitochondrial quality control response was impaired in HFpEF hearts. Using a human induced pluripotent stem cell-derived cardiomyocyte mitophagy reporter, we found that fatty acid loading stimulated mitophagy, which was obliterated by inhibiting fatty acid oxidation. Enhancing fatty acid oxidation by deleting ACC2 (acetyl-CoA carboxylase 2) in the heart stimulated mitophagy and improved HFpEF phenotypes. CONCLUSIONS Maladaptation to metabolic stress in HFpEF hearts impairs mitochondrial quality control and contributed to the pathogenesis, which can be improved by stimulating fatty acid oxidation.

中文翻译：

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响应代谢应激的钝化心脏线粒体自噬会导致 HFpEF。


背景 代谢重塑和线粒体功能障碍是射血分数降低的心力衰竭的标志。然而，它们在射血分数保留型 HF （HFpEF） 发病机制中的作用知之甚少。方法 在高脂饮食和 Nω-硝基-精氨酸甲酯诱导的 HFpEF 小鼠模型中，通过 31P 核磁共振 （NMR） 波谱测量心脏能量学，并通过 13C-同位素分析评估底物氧化曲线。在心脏组织和人诱导的多能干细胞衍生的心肌细胞中评估线粒体功能。结果 HFpEF 心脏的磷酸肌酸含量较低，磷酸肌酸/ATP 比值降低，与射血分数降低的心力衰竭相似。在从 HFpEF 心脏分离的线粒体中观察到呼吸功能下降和活性氧产生增加，表明线粒体功能障碍。心脏底物氧化谱显示 HFpEF 心脏对脂肪酸氧化的高度依赖性，这与射血分数降低的心力衰竭相反，但与高脂肪饮食心脏相似。然而，磷酸肌酸/ATP 比率和线粒体功能在高脂肪饮食心脏中是持续的。我们发现线粒体自噬在高脂肪饮食心脏中被激活，但在 HFpEF 心脏中未被激活，尽管肥胖程度相似，这表明线粒体质量控制反应在 HFpEF 心脏中受损。使用人诱导的多能干细胞衍生的心肌细胞线粒体自噬报告基因，我们发现脂肪酸负荷刺激线粒体自噬，而线粒体自噬则被抑制脂肪酸氧化而消失。 通过删除心脏中的 ACC2 （乙酰辅酶 A 羧化酶 2） 来增强脂肪酸氧化，刺激线粒体自噬并改善 HFpEF 表型。结论 HFpEF 心脏对代谢应激的适应不良损害了线粒体质量控制，并促进了发病机制，这可以通过刺激脂肪酸氧化来改善。