Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada T6G 2S2.
Cardiovasc Res. 2014 Jan 1;101(1):30-8. doi: 10.1093/cvr/cvt216. Epub 2013 Sep 17.
To determine whether post-infarction LV dysfunction is due to low energy availability or inefficient energy utilization, we compared energy metabolism in normal and failing hearts. We also studied whether improved coupling of glycolysis and glucose oxidation by knockout of malonyl CoA decarboxylase (MCD-KO) would have beneficial effects on LV function and efficiency.
Male C57BL/6 mice were subjected to coronary artery ligation (CAL) or sham operation (SHAM) procedure. After 4 weeks and echocardiographic evaluation, hearts were perfused (working mode) to measure LV function and rates of energy metabolism. Similar protocols using MCD-KO mice and wild-type (WT) littermates were used to assess consequences of MCD deficiency. Relative to SHAM, CAL hearts had impaired LV function [lower % ejection fraction (%EF, 49%) and LV work (46%)]. CAL hearts had higher rates (expressed per LV work) of glycolysis, glucose oxidation, and proton production. LV work per ATP production from exogenous sources was lower in CAL hearts, indicative of inefficient exogenous energy substrate utilization. Fatty acid oxidation rates, ATP, creatine, and creatine phosphate contents were unaffected. Utilization of endogenous substrates, triacylglycerol and glycogen, was similar in CAL and SHAM hearts. MCD-KO CAL hearts had 31% higher %EF compared with that of WT-CAL, and lower rates of glycolysis, glucose oxidation, proton production, and ATP production, indicative of improved efficiency.
CAL hearts are inefficient in utilizing energy for mechanical function, possibly due to higher proton production arising from mismatched glycolysis and glucose oxidation. MCD deficiency lessens proton production, LV dysfunction, and inefficiency of exogenous energy substrate utilization.
为了确定心肌梗死后左心室功能障碍是由于能量供应不足还是能量利用效率低下，我们比较了正常和衰竭心脏的能量代谢。我们还研究了通过敲除丙二酰辅酶 A 脱羧酶（MCD-KO）是否可以改善糖酵解和葡萄糖氧化的偶联，从而对左心室功能和效率产生有益影响。
雄性 C57BL/6 小鼠接受冠状动脉结扎（CAL）或假手术（SHAM）处理。4 周后进行超声心动图评估，然后对心脏进行灌注（工作模式）以测量左心室功能和能量代谢率。使用 MCD-KO 小鼠和野生型（WT）同窝仔鼠进行类似的方案，以评估 MCD 缺乏的后果。与 SHAM 相比，CAL 心脏的左心室功能受损[射血分数（%EF）较低（49%）和左心室做功（46%）]。CAL 心脏的糖酵解、葡萄糖氧化和质子产生的速率更高（每单位左心室做功表示）。来源于外源性底物的左心室做功每产生一分子 ATP 的效率较低，表明外源性能量底物的利用效率低下。脂肪酸氧化率、ATP、肌酸和磷酸肌酸含量不受影响。CAL 和 SHAM 心脏的内源性底物三酰甘油和糖原的利用情况相似。MCD-KO CAL 心脏的%EF 比 WT-CAL 高 31%，糖酵解、葡萄糖氧化、质子产生和 ATP 产生的速率较低，表明效率提高。
CAL 心脏在利用能量产生机械功能方面效率低下，可能是由于糖酵解和葡萄糖氧化不匹配导致质子产生增加所致。MCD 缺乏可减少质子产生、左心室功能障碍和外源性能量底物利用效率低下。
