Metabolic Phenotype Switch in HJeart Failure

本项目资助的总体主题是心肌能量异常的识别 心力衰竭时发生的代谢异常，以及这些异常对左心室功能的影响 和重塑。严重失代偿的心脏转变为胎儿代谢表型，其特征在于： 下调游离脂肪酸（FFA）氧化和增强葡萄糖氧化。两个重要 问题仍然没有答案：1）不知道这种代谢改变是否是适应性的， 适应不良机制，也不知道它是否在从代偿性心脏到失代偿性心脏的进展中起作用 失败（HF）; 2）负责失败的代谢表型改变的分子机制 人们对心脏了解甚少。我们的初步数据表明，慢性部分抑制FFA氧化， 在扩张型心肌病的犬模型中延迟失代偿的发作。我们还展示了 类维生素A X受体-a（RXRa）的蛋白质表达减少，RXRa是FFA氧化的关键调节因子， 通路，在终末期起搏诱导的HF中。本项目的总体目标是检验以下假设： RXRa及其专性共受体过氧化物酶体增殖物的表达和活化的变化 受体-a（PPARa）是HF心肌代谢表型改变的关键决定因素， 在心脏代偿失调的进展中起重要作用。研究将在犬中进行， 起搏诱导的HF。第一个具体的目的是确定心肌细胞的变化的时间过程， 代谢表型和蛋白质表达和激活的RXR α和PPARa在连续时间 HF进展期间和起搏后恢复后的时间点。血液动力学变化，心脏 在体内测量的功能和底物代谢将与细胞的关键酶的活性相关。 底物氧化途径以及RXR α、PPARa的表达和活化状态， 快速冷冻的心脏活检。第二个具体目标是确定是否早期心肌转换为 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。的 第三个具体目标是确定RXR α或PPARa的持续激活是否可以防止 心肌代谢表型的改变并加速HF的进展。RXRa和PPARa 在HF发展过程中被给予的特异性配体激活。

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.