Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-alpha in Pacing-Induced Heart Failure
Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-alpha in Pacing-Induced Heart Failure
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作者：
J. C. Gomez
核受体过氧化物酶体增殖物激活受体（cid：1）（PPAR（cid：1））和类维生素A X受体（cid：1）（RXR（cid：1））刺激游离脂肪酸（FFA）氧化的关键酶的表达。我们检验了衰竭心脏的代谢表型改变涉及PPAR（cid：1）和RXR（cid：1）蛋白表达变化的假设。方法和结果-通过输注3种同位素标记的底物：3 H-油酸、14 C-葡萄糖和13 C-乳酸，测量了8只有意识的、长期装有仪器的失代偿起搏诱导心力衰竭犬和8只正常犬的心脏底物摄取和氧化。虽然两组心肌耗氧量无差异，但衰竭组FFA氧化速率低于正常组（2.8（cid：1）0.6 vs4.7（cid：1）0.3（cid：2）mol · min（cid：2）1 ·100 g（cid：2）1），葡萄糖氧化速率高于正常组（4.6（cid：1）1.0 vs1.8（cid：1）0.5（cid：2）mol · min（cid：2）1 ·100 g（cid：2）1）（P（cid：3）0.05）。乳酸摄取率和乳酸输出率在两组之间没有显著差异。在衰竭心脏的左心室组织中，FFA氧化的2种关键酶活性显著降低：肉毒碱棕榈酰转移酶-I（0.54（cid：1）0.04 vs.0.66（cid：1）0.04（cid：2）mol · min（cid：2）1 · g（cid：2）1）和中链酰基辅酶A脱氢酶（MCAD; 1.8（cid：1）0.1 vs.2.9（cid：1）0.3（cid：2）mol · min（cid：2）1 · g（cid：2）1）。结论：心衰组MCAD和RXR（cid：1）蛋白表达均较对照组降低38%，而PPAR（cid：1）蛋白表达无明显差异。RXR（cid：1）的表达与MCAD的表达及活性相关。结论：我们的研究结果首次提供了RXR（cid：1）表达减少与严重心力衰竭代谢表型转换之间联系的证据。（循环。2002;106：606-612）。
Background —The nuclear receptors peroxisome proliferator-activated receptor- (cid:1) (PPAR (cid:1) ) and retinoid X receptor (cid:1) (RXR (cid:1) ) stimulate the expression of key enzymes of free fatty acid (FFA) oxidation. We tested the hypothesis that the altered metabolic phenotype of the failing heart involves changes in the protein expression of PPAR (cid:1) and RXR (cid:1) . Methods and Results —Cardiac substrate uptake and oxidation were measured in 8 conscious, chronically instrumented dogs with decompensated pacing-induced heart failure and in 8 normal dogs by infusing 3 isotopically labeled substrates: 3 H-oleate, 14 C-glucose, and 13 C-lactate. Although myocardial O 2 consumption was not different between the 2 groups, the rate of oxidation of FFA was lower (2.8 (cid:1) 0.6 versus 4.7 (cid:1) 0.3 (cid:2) mol · min (cid:2) 1 · 100g (cid:2) 1 ) and of glucose was higher (4.6 (cid:1) 1.0 versus 1.8 (cid:1) 0.5 (cid:2) mol · min (cid:2) 1 · 100g (cid:2) 1 ) in failing compared with normal hearts ( P (cid:3) 0.05). The rates of lactate uptake and lactate output were not significantly different between the 2 groups. In left ventricular tissue from failing hearts, the activity of 2 key enzymes of FFA oxidation was significantly reduced: carnitine palmitoyl transferase-I (0.54 (cid:1) 0.04 versus 0.66 (cid:1) 0.04 (cid:2) mol · min (cid:2) 1 · g (cid:2) 1 ) and medium chain acyl-coenzyme A dehydrogenase (MCAD; 1.8 (cid:1) 0.1 versus 2.9 (cid:1) 0.3 (cid:2) mol · min (cid:2) 1 · g (cid:2) 1 ). Consistently, the protein expression of MCAD and of RXR (cid:1) were significantly reduced by 38% in failing hearts, but the expression of PPAR (cid:1) was not different. Moreover, there were significant correlations between the expression of RXR (cid:1) and the expression and activity of MCAD. Conclusions —Our results provide the first evidence for a link between the reduced expression of RXR (cid:1) and the switch in metabolic phenotype in severe heart failure. ( Circulation . 2002;106:606-612.)