School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King's College London, The Rayne Institute, St Thomas' Hospital, London, UK.
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
Nat Commun. 2020 Aug 28;11(1):4337. doi: 10.1038/s41467-020-18160-x.
Intracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodelling occurs. Here, we assess whether acute (75 μM ouabain 100 nM blebbistatin) or chronic myocardial Na load (PLM mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic 'fingerprint'. Control (PLM), transgenic (PLM), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by Na, P, C NMR followed by H-NMR metabolomic profiling. Elevated Na leads to common adaptive metabolic alterations preceding energetic impairment: a switch from fatty acid to carbohydrate metabolism and changes in steady-state metabolite concentrations (glycolytic, anaplerotic, Krebs cycle intermediates). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 ameliorates the metabolic changes. In silico modelling indicates altered metabolic fluxes (Krebs cycle, fatty acid, carbohydrate, amino acid metabolism). Prevention of Na overload or inhibition of Na/Ca may be a new approach to ameliorate metabolic dysregulation in heart failure.
心肌细胞内钠离子浓度升高是发生急性和慢性代谢重构的病理特征。在这里，我们评估急性（100nM 哇巴因，75μM 白屈菜红碱，100nM blebbistatin）或慢性心肌钠离子负荷（PLM 小鼠）是否与代谢重构有关，以及衰竭的心脏是否具有共同的钠离子介导的代谢“指纹”。采用 Na、P、C NMR 结合 H-NMR 代谢组学分析方法，研究了对照组（PLM）、转基因组（PLM）、哇巴因处理组和肥厚的 Langendorff 灌流鼠心。钠离子升高导致能量损伤前发生共同的适应性代谢改变：从脂肪酸代谢向碳水化合物代谢转变，以及稳态代谢物浓度变化（糖酵解、回补途径、三羧酸循环中间产物）。线粒体钠钙交换抑制剂 CGP37157 可改善代谢变化。计算机模拟表明代谢通量发生改变（三羧酸循环、脂肪酸、碳水化合物、氨基酸代谢）。预防钠离子过载或抑制钠钙可能是改善心力衰竭代谢失调的新方法。
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