Elevated expression of the metabolic regulator receptor-interacting protein 140 results in cardiac hypertrophy and impaired cardiac function
Elevated expression of the metabolic regulator receptor-interacting protein 140 results in cardiac hypertrophy and impaired cardiac function
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DOI：
10.1093/cvr/cvp418
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发表时间：
2010-06-01
影响因子：
10.8
通讯作者：
White, Roger
中科院分区：
文献类型：
--
作者：
Fritah, Asmaa;Steel, Jennifer H.;White, Roger
受体相互作用蛋白140 （Receptor-interacting protein 140, RIP140）是核受体的一种配体依赖性辅因子，可调节参与细胞过程（包括代谢）的基因网络。RIP140在代谢控制中的重要作用已经在RIP140缺失的小鼠中被发现，其表型包括脂肪细胞中参与能量动员或分解代谢的基因的抑制，以及骨骼肌中更多氧化纤维的转换。我们假设RIP140的普遍表达会抑制代谢过程，导致发育或细胞功能缺陷。在转基因小鼠中外源表达RIP140 mRNA （real-time PCR）和蛋白（western blotting）的主要影响是损害出生后心脏功能。在显微镜下，从4周龄开始，雄性RIP140转基因小鼠出现心肌肥厚和心室纤维化的快速发作，5个月时死亡率为25%。RIP140在心脏中的外源表达导致线粒体状态III和状态IV膜电位和耗氧量下降。定量PCR显示，参与线粒体活性和脂肪酸代谢的基因表达减少了50%以上，包括线粒体转录因子A、细胞色素氧化酶VIIa、细胞色素XII、CD36、中链酰基脱氢酶和脂肪酸转运蛋白，其中许多是已知的核受体靶标，包括过氧化物酶体增殖体激活受体PPAR α和PPAR δ以及雌激素相关受体ERR α和ERR γ。本研究表明，RIP140是产后心功能的重要辅助因子，抑制RIP140的作用可能为研究旨在预防或延迟心脏病发作的特定干预措施提供模型系统。
Receptor-interacting protein 140 (RIP140) is a ligand-dependent cofactor for nuclear receptors that regulate networks of genes involved in cellular processes, including metabolism. An important role for RIP140 in metabolic control has been identified in RIP140 null mice, whose phenotypes include derepression of genes involved in energy mobilization or catabolism in adipocytes and a switch to more oxidative fibres in skeletal muscle. We hypothesized that ubiquitous expression of RIP140 would suppress metabolic processes, leading to defects in development or cellular function.The primary effect of exogenous expression of RIP140 mRNA (real-time PCR) and protein (western blotting) in transgenic mice is impaired postnatal heart function. There was rapid onset of cardiac hypertrophy and ventricular fibrosis, detected microscopically, in male RIP140 transgenic mice from 4 weeks of age, resulting in 25% mortality by 5 months. RIP140 exogenous expression in the heart leads to decreased mitochondria state III and state IV membrane potential and oxygen consumption. Quantitative PCR showed more than 50% reduced expression of genes involved in mitochondrial activity and fatty acid metabolism, including mitochondrial transcription factor A, cytochrome oxidase VIIa, cytochrome XII, CD36, medium-chain acyl dehydrogenase, and fatty acid transport protein, many of which are known targets for nuclear receptors, including peroxisome proliferator-activated receptors PPAR alpha and PPAR delta and oestrogen-related receptors ERR alpha and ERR gamma.This study demonstrates that RIP140 is an important cofactor in postnatal cardiac function and that inhibition of the action of RIP140 may provide a model system to investigate specific interventions designed to prevent or delay the onset of cardiac disease.