Metabolic Phenotype Switch in HJeart Failure

本计划项目资助的总主题是识别心肌能量异常 心力衰竭时的代谢以及这些异常对左心功能的影响 和改建。严重代偿失调的心脏转变为胎儿代谢表型，其特征是 下调游离脂肪酸(FFA)氧化，增强葡萄糖氧化。两个重要的因素 问题仍未得到解答：1)尚不清楚这种代谢变化是适应性的还是 适应不良的机制，也不是它在从代偿到失代偿心脏的进展中起作用 衰竭(HF)；2)衰竭患者代谢表型改变的分子机制 人们对心脏知之甚少。我们的初步数据表明，慢性部分抑制FFA氧化 延缓扩张型心肌病犬模型失代偿的发生。我们还展示了一个 FFA氧化关键调节因子维甲酸X受体-a(RXRA)蛋白表达的降低 在终末期起搏诱导的心衰中。该项目的总体目标是测试以下假设 RXRA及其专性共受体过氧化物酶体增殖物表达和激活的变化 受体-a(PPARa)是心力衰竭心肌代谢表型改变的关键决定因素，在心力衰竭中发挥重要作用。 在心脏失代偿进展过程中起着重要作用。研究将在狗身上进行， 起搏诱发的心衰。第一个具体目标是确定心肌细胞改变的时间进程。 RXRA和PPARa在序贯时间的代谢表型及其蛋白表达和激活 心衰进展期间和起搏后恢复后的时间点。血流动力学、心脏的变化 在体内测量的功能和底物代谢将与关键酶的活性相关 底物氧化途径及其与RXRA、PPARa表达和激活状态的关系 快速冷冻的心脏活组织检查。第二个具体目标是确定早期心肌是否会切换到 碳水化合物的优先氧化延缓了HF的进展。在HF的发展过程中， 心肌FFA氧化将在线粒体前或线粒体内水平被部分抑制。这个 第三个具体目标是确定RXRA或PPARa的持续激活是否可以防止 心肌代谢表型的改变和加速心力衰竭的进展。RXRA和PPARa 将被在HF形成过程中给予的特定配体交替激活。

The overall theme of this Program Project Grant is the identification of abnormalities of myocardial energy metabolism that occur with heart failure, and the effects of these abnormalities on left ventricular function and remodeling. The severely decompensated heart switches to a fetal metabolic phenotype, characterized by downregulation of free fatty acid (FFA) oxidation and enhancement of glucose oxidation. Two important questions remain unanswered: 1) it is not known whether this metabolic alteration is an adaptive or maladaptive mechanism, nor if it plays a role in the progression from compensated to decompensated heart failure (HF); and 2) the molecular mechanisms responsible for the altered metabolic phenotype of the failing heart are poorly understood. Our preliminary data indicate that chronic partial inhibition of FFA oxidation delays the onset of decompensation in a canine model of dilated cardiomyopathy. We have also shown a reduction in the protein expression of retinoid X receptor-a (RXRa), a key regulator of the FFA oxidative pathway, in end-stage pacing-induced HF. The overall goal of this Project is to test the hypothesis that changes in expression and activation of RXRa and of its obligate co-receptor peroxisome proliferator receptor-a (PPARa) are key determinants of the altered myocardial metabolic phenotype in HF and play an important role in the progression toward cardiac decompensation. Studies will be performed in dogs with pacing-induced HF. The first specific aim is to determine the time course of alterations in myocardial metabolic phenotype and in protein expression and activation of RXRa and PPARa at sequential time points during the progression of HF and after post-pacing recovery. Changes in hemodynamics, cardiac function and substrate metabolism measured in vivo will be correlated with the activity of key enzymes of the substrate oxidative pathways and with the expression and activation state of RXRa, PPARa measured in snap-frozen cardiac biopsies. The second specific aim is to determine whether early myocardial switch to preferential oxidation of carbohydrate delays the progression of HF. During development of HF, myocardial FFA oxidation will be partially suppressed at pre-mitochondrial or intra-mitochondrial level. The third specific aim is to determine whether a sustained activation of RXRa or PPARa can prevent the alterations in myocardial metabolic phenotype and accelerate the progression of HF. RXRa and PPARa will be alternatively activated by specific ligands administered during the development of HF.