Objective

Dyslipidaemia is a major risk factor for myocardial infarction that is known to correlate with atherosclerosis in the coronary arteries. We sought to clarify whether metabolic alterations induced by dyslipidaemia in cardiomyocytes collectively constitute an alternative pathway that escalates myocardial injury.

Methods

Dyslipidaemic apolipoprotein E and low-density lipoprotein receptor (ApoE/LDLR) double knockout (ApoE^−/−/LDLR^−/−) and wild-type C57BL/6 (WT) mice aged six months old were studied. Cardiac injury under reduced oxygen supply was evaluated by 5 min exposure to 5% oxygen in the breathing air under electrocardiogram (ECG) recording and with the assessment of troponin I release. To address the mechanisms LC/MS was used to analyse the cardiac proteome pattern or in vivo metabolism of stable isotope-labelled substrates and HPLC was applied to measure concentrations of cardiac high-energy phosphates. Furthermore, the effect of blocking fatty acid use with ranolazine on the substrate preference and cardiac hypoxic damage was studied in ApoE^−/−/LDLR^−/− mice.

Results

Hypoxia induced profound changes in ECG ST-segment and troponin I leakage in ApoE^−/−/LDLR^−/− mice but not in WT mice. The evaluation of the cardiac proteomic pattern revealed that ApoE^−/−/LDLR^−/− as compared with WT mice were characterised by coordinated increased expression of mitochondrial proteins, including enzymes of fatty acids' and branched-chain amino acids' oxidation, accompanied by decreased expression levels of glycolytic enzymes. These findings correlated with in vivo analysis, revealing a reduction in the entry of glucose and enhanced entry of leucine into the cardiac Krebs cycle, with the cardiac high-energy phosphates pool maintained. These changes were accompanied by the activation of molecular targets controlling mitochondrial metabolism. Ranolazine reversed the oxidative metabolic shift in ApoE^−/−/LDLR^−/− mice and reduced cardiac damage induced by hypoxia.

Conclusions

We suggest a novel mechanism for myocardial injury in dyslipidaemia that is consequent to an increased reliance on oxidative metabolism in the heart. The alterations in the metabolic pattern that we identified constitute an adaptive mechanism that facilitates maintenance of metabolic equilibrium and cardiac function under normoxia. However, this adaptation could account for myocardial injury even in a mild reduction of oxygen supply.

中文翻译：

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动脉粥样硬化性血脂异常的心脏缺氧性损伤增加是由于能量代谢方式的改变

目的

血脂异常是心肌梗塞的主要危险因素，已知与冠状动脉的动脉粥样硬化相关。我们试图阐明由血脂异常引起的心肌细胞代谢改变是否共同构成了升级心肌损伤的替代途径。

方法

研究了血脂异常的载脂蛋白E和低密度脂蛋白受体（ApoE / LDLR）双敲除（ApoE ^-/- / LDLR ^-/-）和六个月大的野生型C57BL / 6（WT）小鼠。通过在心电图（ECG）记录下呼吸空气中暴露于5％的氧气5分钟并评估肌钙蛋白I释放来评估氧气供应减少时的心脏损伤。为了解决该机制，LC / MS用于分析心脏蛋白质组模式或稳定同位素标记的底物的体内代谢，并且HPLC用于测量心脏高能磷酸盐的浓度。此外，在ApoE ^-/- / LDLR ^-/-中研究了雷诺嗪对脂肪酸使用的阻断作用对底物偏好和心脏缺氧损伤的影响^。 老鼠。

结果

低氧在ApoE ^-/- / LDLR ^-/-小鼠中引起ECG ST段和肌钙蛋白I渗漏的深刻变化，而在WT小鼠中则没有。对心脏蛋白质组学模式的评估表明，与WT小鼠相比，ApoE ^-/- / LDLR ^-/-的特征在于线粒体蛋白（包括脂肪酸酶和支链氨基酸的氧化）的协同表达增加，并伴有糖酵解酶的表达水平降低。这些发现与体内相关分析表明，在保持心脏高能磷酸盐池的情况下，葡萄糖的减少和亮氨酸进入心脏Krebs循环的增加。这些变化伴随着控制线粒体代谢的分子靶标的激活。雷诺嗪逆转了ApoE ^-/- / LDLR ^-/-小鼠的氧化代谢转变，并减少了由缺氧引起的心脏损害。

结论

我们建议在血脂异常中心肌损伤的一种新机制，从而增加了对心脏氧化代谢的依赖性。我们确定的代谢模式改变构成了一种适应性机制，可促进在常氧下维持代谢平衡和心脏功能。但是，即使适度减少供氧量，这种适应也可以解决心肌损伤。