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Structure and function of novel genes which differentially expressed in cardiac hypertrophy of carnitine deficiency

肉碱缺乏性心脏肥大差异表达新基因的结构和功能

基本信息

批准号：
10470042
负责人：
SAHEKI Takeyori
金额：
$ 8.51万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2001
项目状态：
已结题

项目摘要

Carnitine is an essential co factor for β-oxidation of long-chain fatty acids. Juvenile visceral steatosis (JVS) mice have been reported as an animal model for Reye-like syndrome in 1988, suffering from fatty liver, hypoglycemia, hyperammonemia and growth retardation. Then, the mice have been established as an animal model for systemic carnitine deficiency caused by a defect of plasma membrane carnitine transport protein, Octn2. One of the most notable symptoms of the mice is cardiac hypertrophy. In the present study, we characterized the structure and function of three novel genes which differentially expressed in the ventricles of JVS mice, CDV-1, -2, and -3 (carnitine-deficiency-associated genes expressed in ventricle). CDV-1 is heart-specific gene and specifically suppressed in the hypertrophied ventricles of JVS mice, while CDV-1R is CDV-1 related gene which is expressed not only in the heart but also in the kidney and brain and not differentially expressed. CDV-1 mRNA is constructed from the 3'-half of CDV-1R and the presumed promoter sequence for CDV-1 locates in the intron 14. CDV-2 is highly expressed in the ventricles of JVS mice and was found to be a mouse homolog of pyruvate dehydrogenase kinase 4 (PDK4). The cardiac expression of CDV-3 is also augmented in the ventricles of JVS mice and suppressed by the carnitine treatment. The sequence analysis revealed that CDV-3 has a high similarity to a human predicted nuclear protein (H41) which has been reported to be up-regulated in breast cancer cells overexpressed c-erbB-2 (a kind of tyrosine kinase). These results suggest that CDV-1 and CDV-3 are directly involved in cardiac hypertrophy and CDV-2, or PDK4, is more related to carnitine deficiency. Effect of dietary lipid on the development of cardiac hypertrophy is also reported.

肉毒碱是长链脂肪酸β-氧化的重要辅助因子。1988年，幼年内脏脂肪变性（JVS）小鼠被报道为Reye样综合征的动物模型，其患有脂肪肝、低血糖、高氨血症和生长迟缓。然后，将小鼠建立为由质膜肉毒碱转运蛋白Octn 2缺陷引起的全身性肉毒碱缺乏症的动物模型。小鼠最显著的症状之一是心脏肥大。在本研究中，我们确定了在JVS小鼠心室中差异表达的三个新基因，CDV-1，CDV-2和CDV-3（心室中表达的肉毒碱缺乏相关基因）的结构和功能。CDV-1是心脏特异性基因，在JVS小鼠肥大的心室中特异性抑制，而CDV-1 R是CDV-1相关基因，不仅在心脏中表达，而且在肾脏和脑中也表达，且表达无差异。CDV-1 mRNA由CDV-1 R的3 ′-半部分构建，CDV-1的假定启动子序列位于内含子14。CDV-2在JVS小鼠的心室中高度表达，并且被发现是丙酮酸脱氢酶激酶4（PDK 4）的小鼠同源物。CDV-3的心脏表达也在JVS小鼠的心室中增加，并且被肉毒碱处理抑制。序列分析显示，CDV-3与人类预测的核蛋白（H41）具有高度相似性，据报道，H41在过表达c-erbB-2（一种酪氨酸激酶）的乳腺癌细胞中上调。这些结果表明，CDV-1和CDV-3直接参与心肌肥厚，CDV-2或PDK 4与肉毒碱缺乏更相关。膳食脂质对心肌肥厚的影响也有报道。