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Molecular Biology of Vasoactive Substances

血管活性物质的分子生物学

基本信息

批准号：
06404037
负责人：
NAKAO Kazuwa
金额：
$ 22.21万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

We isolated mouse BNP cDNA and genomic clones, and generated transgenic mice with elevated plasma BNP concentration accompanied with high plasam c GMP concentration. These mice provide a useful model system to assess the roles of BNP.We also isolated hamster BNP and ANP cDNAs to examine pathophysiological roles of natriuretic peptides in cardiomyopathic hamsters. Using cultured rat vascular smmoth muscle cells, we demonstrated that the beta2-adrenergic receptor stimulation duwnregulates the C receptor through the decrease in the transcriptional rate of the C receptor gene and that the activation of sympathetic nervous system augments the biological responsiveness to natriuretic peptides by attenuating their metabolic clearance in vascular walls. The concentration of CNP in the medium was incresed 60 fold in the vascular endothelial cell/vascular smooth muscle cell coculture with direct contact compared with that in endothelial cell alone. We demonstrated that the augmented production of CNP in the coculture is in part regulated by TGF-beta.We isolated two novel transcripts of human endothelin A receptor gene, which contained deletion of exon 4 and 3 and exon 4 resulting from alternative RNA splicing. These transcripts were observed in various human tissues suggesting that this alternative RNA splicing might contribute to the regulation of endothelin A receptor gene expression.We cloned human prostacyclin receptor cDNA and elucidated its abundant gene expression in the cardiovascular system. We also isolated five distinct cDNA clones of human PGE receptor EP_3 subtype and revealed the presence of multiple signal transduction systems of PGE/EP_3 isoform.

我们分离小鼠BNP cDNA和基因组克隆，获得血浆BNP浓度升高并伴有血浆c - GMP浓度升高的转基因小鼠。这些小鼠为评估BNP的作用提供了一个有用的模型系统。我们还分离了仓鼠BNP和ANP cdna来检测利钠肽在心肌病仓鼠中的病理生理作用。利用培养的大鼠血管平滑肌细胞，我们证明β -肾上腺素能受体刺激通过降低C受体基因的转录率而下调C受体，并且交感神经系统的激活通过减弱利钠肽在血管壁的代谢清除来增强对利钠肽的生物反应。血管内皮细胞/血管平滑肌细胞直接接触共培养时，培养液中CNP浓度比内皮细胞单独培养时提高了60倍。我们证明了共培养中CNP的增加部分受到tgf - β的调节。我们分离了两个新的人内皮素A受体基因转录本，它们包含由选择性RNA剪接导致的外显子4和3和外显子4的缺失。这些转录本在各种人体组织中被观察到，表明这种选择性RNA剪接可能有助于调节内皮素A受体基因的表达。我们克隆了人前列环素受体cDNA，并阐明了其在心血管系统中的丰富表达。我们还分离到5个不同的人类PGE受体EP_3亚型cDNA克隆，发现存在PGE/EP_3亚型的多个信号转导系统。