ROLE OF CELL CYCLE REGULATED GENES AND TUMOR SUPRESSOR GENES IN TERMINAL DIFFERENTIATION OF CARDIOMYOCYTES.

细胞周期调节基因和肿瘤抑制基因在心肌细胞终末分化中的作用。

基本信息

批准号：
09670749
负责人：
FUKUDA Keiichi
金额：
$ 2.24万
依托单位：
KEIO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670749/
关键词：
CARDIOMYOCYTE TERMINAL DIFFERENTIATION CELL CYCLE AT-1 CELL CYCLIN TUMOR SUPPRESOR GENES Cardiomyocyte mitogenesity AngiotensinII Candionyocyte terminal diflerentiation Cyclirl cdk Tumor supllressor

项目摘要

Angiotensin II has been shown tobe mitogenic in various cell types. In cultured neonatal cardiomyocytes, we have demonstrated that angiotensin II causes hypertrophy, not hyperplasia. However, fetal or neonatal cardiomyocytes exhibit limited proliferation in primary culture, and are mitotically less potent. In order to determine whether angiotensin II is simply a hypertrophic or hyperplastic growth factor for mitotically potent cardiomyocytes, we analyzed [^3H]-Thymidine uptake and cell cycle-regulated gene expression using SV4O large T-transformed AT-1 cardiomyocytes. Angiotensin II, alone and in combination with other growth factors, increased [^3H]-Thymidine uptake in a dose-dependent manner. The mRNA expression of G1 cyclin (Cyclin C, Dl, D2, D3) and histone H1-kinase activity by cdk2 increased 6 h after angiotensin II stimulation Westernblot analysis revealed cyclin B1 expression after 18 h, which peaked at 30 h. Histone Hi-kinase activity by cdc2 was also increased by angiotensin II, and peaked at 24 - 36 h, indicating that these changes were cell cycle dependent. Double immunofluorescent photography showed that AT-1 cells incorporated BrdU, and expressed cdc2 by angiotensin II stimulation [^3H]-Thymidine and BrdU uptake were blocked by Losartan, but not by PD123319. Incontrast with neonatal cardiomyocyte, angiotensin II potentiated DNA synthesis and induced cell cycle regulated gene expression in AT-1 cardiomyocytes, and this activity was mediated by the angiotensin II type-1 receptor.

血管紧张素II已显示出各种细胞类型的有丝分裂。在培养的新生儿心肌细胞中，我们已经证明血管紧张素II会引起肥大，而不是增生。然而，胎儿或新生儿心肌细胞在原发性培养中的增殖有限，并且有丝分裂的效力较低。为了确定血管紧张素II只是有丝分裂有效的心肌细胞的肥大或增生生长因子，我们使用SV4O大型T-转移AT-1心肌细胞分析了[^3H]胸腺苷的摄取和细胞周期调节的基因表达。血管紧张素II，单独并与其他生长因子结合使用，以剂量依赖性的方式增加了[^3H] - 胸腺苷的摄取。 G1细胞周期蛋白（Cyclin C，DL，D2，D3）和组蛋白H1-激酶活性的mRNA表达在血管紧张素II刺激Westernblot分析后6小时增加了Cyclin b1表达后18小时表达，在30小时达到峰值。血管紧张素II还增加了CDC2的组蛋白HI-激酶活性，并在24-36小时达到峰值，表明这些变化取决于细胞周期。双重免疫荧光摄影表明，AT-1细胞掺入BRDU，并通过血管紧张素II刺激[^3H] - 胸苷和BRDU摄取表达Cdc2，而Losartan则被PD123319封闭。与新生儿心肌细胞，血管紧张素II增强的DNA合成和诱导细胞周期调节的AT-1心肌细胞基因表达的对立，该活性是由血管紧张素II型1受体介导的。

项目成果

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Jing Pan, Keiichi Fnkuda, Mikiyoshi Saito, Junichi Matsuzaki, Hiroaki Kodama, Motoaki Sano, Toshiyuki Takahashi, Takahiro Kato, Satoshi Ogawa: "Mechanical Stretch Activates the JAK/STAT Pathway in Rat Cardi omyocytes." Circ.Res.(in press). (1999)

Jing Pan、Keiichi Fnkuda、Mikiyoshi Saito、Junichi Matsuzaki、Hiroaki Kodama、Motoaki Sano、Toshiyuki Takahashi、Takahiro Kato、Satoshi Okawa：“机械拉伸激活大鼠心肌细胞中的 JAK/STAT 通路。”