Fatty acid utilization in the hypertrophied and failing heart: Molecular regulatory mechanisms
Fatty acid utilization in the hypertrophied and failing heart: Molecular regulatory mechanisms
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DOI：
10.1097/00000441-199907000-00006
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发表时间：
1999-07-01
影响因子：
3.1
通讯作者：
Kelly, DP
中科院分区：
文献类型：
--
作者：
Barger, PM;Kelly, DP
在心脏肥大的发展过程中和衰竭的心脏中，主要的心肌能量来源从脂肪酸P-氧化转换为糖酵解：向胎儿能量底物偏好模式的逆转。本文综述了最近的分子研究，旨在阐明参与肥大心脏能量代谢转换的基因调节途径以及随之而来的代谢后果在心力衰竭发病机制中的潜在作用。已经用“自发性高血压和心力衰竭”大鼠品系和人类心肌病组织进行了研究。这些研究表明，在心肌肥厚到心室功能障碍的过程中，编码中链酰基辅酶A脱氢酶（MCAD）（一种关键的脂肪酸P-氧化酶）的基因表达下调。在转基因小鼠的人MCAD基因启动子进行了一系列的研究已经确定了一个转录调控途径参与MCAD基因表达的抑制在肥大的小鼠心脏。两类转录因子，核激素受体和Sp因子，结合MCAD基因启动子调节元件，以响应压力过载，重新激活胎儿代谢基因程序。目前正在进行研究，利用基因工程策略在小鼠中操纵这种转录调节途径，以确定这种能量代谢紊乱是否在心脏肥大和心力衰竭的发展中起主要作用。
During the development of cardiac hypertrophy and in the failing heart, the chief myocardial energy source switches from Fatty acid P-oxidation to glycolysis: a reversion to the fetal energy substrate preference pattern. This review describes recent molecular studies aimed at delineating the gene regulatory pathway involved in the energy metabolic switch in the hypertrophied heart and the potential role of the attendant metabolic consequences in the pathogenesis of heart failure. Studies have been performed with the 'spontaneous hypertensive and heart failure' rat strain and with human cardiomyopathic tissue. These studies have demonstrated that expression of the gene that encodes medium-chain acyl-coenzyme A dehydrogenase (MCAD), a key fatty acid P-oxidation enzyme, is downregulated during the progression from cardiac hypertrophy to ventricular dysfunction. A series of studies performed in mice transgenic for the human MCAD gene promoter have identified a transcriptional regulatory pathway involved in the repression of MCAD gene expression in the hypertrophied mouse heart. Two categories of transcription factors, nuclear hormone receptors and Sp factors, bind MCAD gene promoter regulatory elements in response to pressure overload to reactivate a fetal metabolic gene program. Studies are under way to manipulate this transcriptional regulatory pathway in mice using genetic engineering strategies to determine whether this energy metabolic derangement plays a primary role in the development of cardiac hypertrophy and heart failure.