Pellieux Corinne, Aasum Ellen, Larsen Terje S, Montessuit Christophe, Papageorgiou Irène, Pedrazzini Thierry, Lerch René
Cardiology Center, University Hospitals of Geneva, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland.
J Mol Cell Cardiol. 2006 Sep;41(3):459-66. doi: 10.1016/j.yjmcc.2006.06.004. Epub 2006 Jul 21.
Heart failure is associated with downregulation of the fatty acid oxidation pathway in the ventricular myocardium. Since angiotensin II plays a critical role in myocardial phenotypic changes associated with heart failure, we investigated the effect of chronic angiotensin II stimulation on the fatty acid oxidation pathway in transgenic (TG) mice with targeted overexpression of angiotensinogen in the myocardium (TG1306/1R mice). TG1306/R1 mice progressively developed left ventricular hypertrophy. After 12 months, approximately half of the mice exhibited signs of heart failure including increased lung weight index [>+2 SD of age-matched wild-type (WT) mice] and 5-fold increase of myocardial brain natriuretic peptide expression. Myocardial mRNA and protein expression of peroxisome proliferator-activated receptor alpha (PPARalpha) progressively decreased in both WT and TG1306/R1 mice during the 12 months observation period, but much more pronounced in TG1306/R1 mice. Concomitantly, mRNA expression of enzymes of fatty acid oxidation (medium-chain acyl CoA dehydrogenase, MCAD; carnitine palmitoyl transferase I, CPT-I) was reduced in TG1306/R1 compared with age-matched WT mice. However, protein expression of MCAD and CPT-I was decreased concomitantly only in TG mice with criteria of heart failure. Correspondingly, myocardial oxidation of palmitate, measured during ex vivo working heart perfusion, was reduced by 25% in TG1306/R1 mice with heart failure. These results demonstrate that angiotensin II-induced cardiac hypertrophy is associated with reduction of PPARalpha and of mRNA expression of enzymes of fatty acid metabolism relative to age-matched WT mice. However, both protein expression of fatty acid oxidation enzymes and the rate of fatty acid oxidation remain unchanged unless heart failure occurs, suggesting the involvement of posttranscriptional mechanisms in the metabolic changes associated with heart failure.
心力衰竭与心室心肌中脂肪酸氧化途径的下调有关。由于血管紧张素II在与心力衰竭相关的心肌表型变化中起关键作用，我们研究了慢性血管紧张素II刺激对心肌中血管紧张素原靶向过表达的转基因（TG）小鼠（TG1306/1R小鼠）脂肪酸氧化途径的影响。TG1306/R1小鼠逐渐发展为左心室肥厚。12个月后，大约一半的小鼠出现心力衰竭迹象，包括肺重量指数增加[>年龄匹配的野生型（WT）小鼠的+2标准差]和心肌脑钠肽表达增加5倍。在12个月的观察期内，WT和TG1306/R1小鼠心肌中过氧化物酶体增殖物激活受体α（PPARα）的mRNA和蛋白质表达均逐渐降低，但在TG1306/R1小鼠中更为明显。同时，与年龄匹配的WT小鼠相比，TG1306/R1小鼠中脂肪酸氧化酶（中链酰基辅酶A脱氢酶，MCAD；肉碱棕榈酰转移酶I，CPT-I）的mRNA表达降低。然而，仅在符合心力衰竭标准的TG小鼠中，MCAD和CPT-I的蛋白质表达同时降低。相应地，在离体工作心脏灌注期间测量的TG1306/R1心力衰竭小鼠中棕榈酸的心肌氧化减少了25%。这些结果表明，与年龄匹配的WT小鼠相比，血管紧张素II诱导的心脏肥大与PPARα以及脂肪酸代谢酶的mRNA表达降低有关。然而，除非发生心力衰竭，脂肪酸氧化酶的蛋白质表达和脂肪酸氧化速率均保持不变，这表明转录后机制参与了与心力衰竭相关的代谢变化。
