Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription
Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription
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DOI：
10.1152/ajpheart.00319.2008
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发表时间：
2008-09-01
影响因子：
4.8
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Fang, Cindy X.;Dong, Feng;Ren, Jun
细胞肥大受到协调的促生长和抗生长机制的调节。 Foxo 转录因子启动一个与萎缩相关的基因程序来对抗肥大性生长。 This study was designed to evaluate the role of Akt, the forkhead transcription factor Foxo3a, and atrophy genes muscle-specific RING finger (MuRF)-1 and atrogin-1 in cardiac hypertrophy and contractile dysfunction associated with high-fat diet-induced obesity.小鼠被喂食低脂肪或高脂肪饮食 6 个月，对照组则喂食限制食物的高脂肪饮食。超声心动图显示，高脂肪肥胖小鼠的缩短分数减少，收缩末期直径增加，心脏肥大，但体重对照小鼠则不然。来自高脂肪肥胖小鼠而非体重对照小鼠的心肌细胞表现出收缩和细胞内 Ca2+ 缺陷，包括缩短/再延长的最大速度降低、缩短/再延长的持续时间延长以及细胞内 Ca2+ 升高和清除减少。半胱天冬酶活性在高脂肪肥胖小鼠心脏中较高，但在体重控制小鼠心脏中则不然。 Western blot analysis revealed enhanced basal Akt and Foxo3a phosphorylation and reduced insulin-stimulated phosphorylation of Akt and Foxo3a without changes in total protein expression of Akt and Foxo3a in high-fat obese hearts. RT-PCR 和免疫印迹结果显示，在高脂肪肥胖小鼠心脏中，雄激素 atrogin-1 和 MuRF-1 的水平降低，肥大标记物 GATA4 和睫状神经营养因子受体-α 上调，以及未改变的钙调神经磷酸酶和蛋白酶体泛素水平降低。 Transfection of H9C2 myoblast cells with dominant-negative Foxo3a adenovirus mimicked palmitic acid (0.8 mM for 24 h)-induced GATA4 upregulation without an additive effect.显性失活 Foxo3a 诱导的 pAkt 上调以及磷酸酶和张力蛋白同源物的抑制可被棕榈酸消除。 These results suggest a cardiac hypertrophic response in high-fat diet-associated obesity at least in part through inactivation of Foxo3a by the Akt pathway.
Cellular hypertrophy is regulated by coordinated pro- and antigrowth machineries. Foxo transcription factors initiate an atrophy-related gene program to counter hypertrophic growth. This study was designed to evaluate the role of Akt, the forkhead transcription factor Foxo3a, and atrophy genes muscle-specific RING finger (MuRF)-1 and atrogin-1 in cardiac hypertrophy and contractile dysfunction associated with high-fat diet-induced obesity. Mice were fed a low-or high-fat diet for 6 mo along with a food-restricted high-fat weight control group. Echocardiography revealed decreased fractional shortening and increased end-systolic diameter and cardiac hypertrophy in high-fat obese but not in weight control mice. Cardiomyocytes from high-fat obese but not from weight control mice displayed contractile and intracellular Ca2+ defects including depressed maximal velocity of shortening/relengthening, prolonged duration of shortening/relengthening, and reduced intracellular Ca2+ rise and clearance. Caspase activities were greater in high-fat obese but not in weight control mouse hearts. Western blot analysis revealed enhanced basal Akt and Foxo3a phosphorylation and reduced insulin-stimulated phosphorylation of Akt and Foxo3a without changes in total protein expression of Akt and Foxo3a in high-fat obese hearts. RT-PCR and immunoblotting results displayed reduced levels of the atrogens atrogin-1 and MuRF-1, the upregulated hypertrophic markers GATA4 and ciliary neurotrophic factor receptor-alpha, as well as the unchanged calcineurin and proteasome ubiquitin in high-fat obese mouse hearts. Transfection of H9C2 myoblast cells with dominant-negative Foxo3a adenovirus mimicked palmitic acid (0.8 mM for 24 h)-induced GATA4 upregulation without an additive effect. Dominant-negative Foxo3a-induced upregulation of pAkt and repression of phosphatase and tensin homologue were abrogated by palmitic acid. These results suggest a cardiac hypertrophic response in high-fat diet-associated obesity at least in part through inactivation of Foxo3a by the Akt pathway.