Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy
Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy
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DOI：
10.1161/01.res.0000154079.20681.b9
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发表时间：
2005-02-04
影响因子：
20.1
通讯作者：
Schaffer, JE
中科院分区：
文献类型：
--
作者：
Chiu, HC;Kovacs, A;Schaffer, JE
越来越多的证据表明，全身代谢紊乱可导致心肌细胞功能障碍和临床明显的心力衰竭，而与冠状动脉疾病无关。为了验证心肌细胞脂质稳态紊乱会导致心功能障碍的假设，我们利用α -肌球蛋白重链基因启动子，设计了心肌特异性脂肪酸转运蛋白1 （FATP1）过表达的转基因小鼠。两个独立的转基因品系显示心肌游离脂肪酸（FFA）摄取增加了4倍，这与FATP1的已知功能一致。该模型中增加的FFA摄取可能有助于早期心肌细胞FFA积累（增加2倍）和随后增加的心脏FFA代谢（增加2倍）。到3个月大时，转基因小鼠的超声心动图显示左心室充盈和双房增大受损，但收缩功能保留。多普勒组织成像和血流动力学研究证实，这些小鼠主要有舒张功能障碍。此外，动态心电图监测显示QT(c)间期延长，反映心室肌细胞重极化、电压门控的K+电流密度降低。我们的研究结果表明，在没有全身性代谢紊乱的情况下，如糖尿病或高脂血症，心肌细胞脂质稳态的扰动导致心功能障碍，其病理生理结果与糖尿病性心肌病相似。此外，MHC-FATP模型支持fatp在体内FFA导入心脏中的作用。
Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the alpha-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT(c) intervals, reflecting reductions in the densities of repolarizing, voltage-gated K+ currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.