Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy.
Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy.
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DOI：
10.1161/circresaha.112.268128
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发表时间：
2012-08-31
影响因子：
20.1
通讯作者：
Tian R
中科院分区：
文献类型：
--
作者：
Kolwicz SC Jr;Olson DP;Marney LC;Garcia-Menendez L;Synovec RE;Tian R
脂肪酸氧化（FAO）减少，对葡萄糖的依赖性增加，是病理性心脏肥大中发生的代谢重塑的标志，与心肌能量降低和心脏功能受损相关。迄今为止，尚未测试预防心脏肥大发展期间发生的代谢转换是否对心脏功能和能量学具有明确的益处。由于丙二酰辅酶A生产通过乙酰辅酶A羧化酶2（ACC 2）抑制线粒体脂肪酸转运，我们假设心脏特异性缺失ACC 2（ACC 2 H −/−）的小鼠将维持心脏脂肪酸氧化（FAO），并在压力超负荷肥大的发展过程中改善功能和能量。ACC 2缺失导致心脏丙二酰辅酶A水平显著降低。在离体心脏灌注实验中，ACC 2 H −/−小鼠的左心室（LV）功能和耗氧量相似，尽管与对照组（CON）相比，FAO增加了约60%。通过横主动脉缩窄（TAC）进行8周的压力超负荷后，ACC 2 H −/−小鼠表现出与假手术动物相似的底物利用特征，而CON-TAC心脏的FAO减少，糖酵解和回补增加。在8周的TAC后，通过31 P NMR光谱评估的心肌能量学和心脏功能在ACC 2 H −/−中得以维持。此外，ACC 2 H −/−-TAC显示了心脏肥大的衰减，相对于CON-TAC，纤维化显著减少。这些数据表明，在慢性病理性肥大中，胎儿代谢谱的逆转与心肌功能和能量受损相关，维持固有的心脏代谢谱和线粒体氧化能力是一种可行的治疗策略。
Decreased fatty acid oxidation (FAO) with increased reliance on glucose are hallmarks of metabolic remodeling that occurs in pathological cardiac hypertrophy and is associated with decreased myocardial energetics and impaired cardiac function. To date, it has not been tested whether prevention of the metabolic switch that occurs during the development of cardiac hypertrophy has unequivocal benefits on cardiac function and energetics. Since malonyl CoA production via acetyl CoA carboxylase 2 (ACC2) inhibits mitochondrial fatty acid transport, we hypothesized that mice with a cardiac-specific deletion of ACC2 (ACC2H−/−) would maintain cardiac fatty acid oxidation (FAO) and improve function and energetics during the development of pressure-overload hypertrophy. ACC2 deletion led to a significant reduction in cardiac malonyl CoA levels. In isolated perfused heart experiments, left ventricular (LV) function and oxygen consumption were similiar in ACC2H−/− mice despite an ~60% increase in FAO compared to controls (CON). After 8 weeks of pressure-overload via transverse aortic constriction (TAC), ACC2H−/− mice exhibited a substrate utilization profile similar to sham animals while CON-TAC hearts had decreased FAO with increased glycolysis and anaplerosis. Myocardial energetics, assessed by 31P NMR spectroscopy, and cardiac function were maintained in ACC2H−/− after 8 weeks of TAC. Furthermore, ACC2H−/−-TAC demonstrated an attenuation of cardiac hypertrophy with a significant reduction in fibrosis relative to CON-TAC. These data suggest that reversion to the fetal metabolic profile in chronic pathological hypertrophy is associated with impaired myocardial function and energetics and maintenance of the inherent cardiac metabolic profile and mitochondrial oxidative capacity is a viable therapeutic strategy.