Diabetic db/db mice do not develop heart failure upon pressure overload: a longitudinal in vivo PET, MRI, and MRS study on cardiac metabolic, structural, and functional adaptations
Diabetic db/db mice do not develop heart failure upon pressure overload: a longitudinal in vivo PET, MRI, and MRS study on cardiac metabolic, structural, and functional adaptations
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DOI：
10.1093/cvr/cvx100
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发表时间：
2017-08-01
影响因子：
10.8
通讯作者：
Prompers, Jeanine J.
中科院分区：
文献类型：
--
作者：
Abdurrachim, Desiree;Nabben, Miranda;Prompers, Jeanine J.
心衰与心肌底物代谢改变和心脏能量功能受损有关。糖尿病等合并症可能影响心力衰竭发展过程中的代谢适应。我们量化了底物偏好、脂质积累和能量状态的变化在多大程度上预测了非糖尿病和糖尿病心脏肥厚和衰竭的纵向发展。方法和结果采用非糖尿病（db/+）和糖尿病（db/db）小鼠主动脉横断收缩术（TAC）诱导压力过载。应用磁共振成像、P-31磁共振波谱（MRS）、H-1磁共振波谱和f -18氟脱氧葡萄糖正电子发射断层扫描（PET）分别测量心功能、能量状态、脂质含量和葡萄糖摄取。体内测量辅以高分辨率呼吸测定法、蛋白质组学和免疫印迹法等体外技术，以阐明潜在的分子途径。在非糖尿病小鼠中，TAC诱导进行性心肌肥厚和功能障碍，这与蛋白激酶D-1 （PKD1）磷酸化增加和葡萄糖摄取增加有关。葡萄糖利用的这些变化先于心脏能量状态的降低。在基线时，与非糖尿病小鼠相比，糖尿病小鼠表现出正常的心功能，更高的脂质含量和线粒体脂肪酸氧化能力，更低的PKD1磷酸化，葡萄糖摄取和能量学。有趣的是，TAC仅轻微影响糖尿病小鼠的心功能，并伴有磷酸化PKD1、葡萄糖摄取和心脏能量状态的正常化。结论糖尿病小鼠的心脏代谢适应似乎可以防止心脏在压力过载时衰竭，提示恢复葡萄糖和脂肪酸利用之间的平衡有利于心脏功能。
Aims Heart failure is associated with altered myocardial substrate metabolism and impaired cardiac energetics. Comorbidities like diabetes may influence the metabolic adaptations during heart failure development. We quantified to what extent changes in substrate preference, lipid accumulation, and energy status predict the longitudinal development of hypertrophy and failure in the non-diabetic and the diabetic heart.Methods and results Transverse aortic constriction (TAC) was performed in non-diabetic (db/+) and diabetic (db/db) mice to induce pressure overload. Magnetic resonance imaging, P-31 magnetic resonance spectroscopy (MRS), H-1 MRS, and F-18-fluorodeoxyglucose-positron emission tomography (PET) were applied to measure cardiac function, energy status, lipid content, and glucose uptake, respectively. In vivo measurements were complemented with ex vivo techniques of high-resolution respirometry, proteomics, and western blotting to elucidate the underlying molecular pathways. In non-diabetic mice, TAC induced progressive cardiac hypertrophy and dysfunction, which correlated with increased protein kinase D-1 (PKD1) phosphorylation and increased glucose uptake. These changes in glucose utilization preceded a reduction in cardiac energy status. At baseline, compared with non-diabetic mice, diabetic mice showed normal cardiac function, higher lipid content and mitochondrial capacity for fatty acid oxidation, and lower PKD1 phosphorylation, glucose uptake, and energetics. Interestingly, TAC affected cardiac function only mildly in diabetic mice, which was accompanied by normalization of phosphorylated PKD1, glucose uptake, and cardiac energy status.Conclusion The cardiac metabolic adaptations in diabetic mice seem to prevent the heart from failing upon pressure overload, suggesting that restoring the balance between glucose and fatty acid utilization is beneficial for cardiac function.