| Project/Area Number |
07557072
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 試験 |
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| Research Field |
内分泌・代謝学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
NAKAO Kazuwa Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Professor, 医学研究科, 教授 (00172263)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Shoji Laboratory of Molecular Pharmacology Suntory Institute of Biomedical Research, G, 部長
KANGAWA Kenji National Cardiovascular Center Research, Department of Biochemistry, Director, 部長 (00112417)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥11,200,000 (Direct Cost: ¥11,200,000)
Fiscal Year 1996: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1995: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | atrial natriuretic peptide / brain natriuretic peptide / C-type natriuretic peptide / cardiac hormone / local regulator / chromosome / gene targeting / ES cells / 心房性ナトリウム利尿パプチド / 心房性ナトリウム利尿ペプチド / 遺伝子欠損マウス / 相同組換え体 |
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| Research Abstract |
The mouse BNP and CNP genes were isolated from a 129Sv mouse genomic library. Targeting vectors for the disruption of BNP or CNP were constructed, in wihch the 2nd and 3rd exons of the BNP gene or the 1st exon of the CNP gene were replaced by the neomycin resistance gene. Several chimeric mice were obtained from the targeted ES cell lines. We are currently mating heterozygotes to obtain mice that are homozygous for the disrupted allele.
We characterized a genomic DNA fragment containing the ANP and BNP genes in mice and humans. In mice, the BNP gene was located about 12kb upstream of the ANP gene. An 11-kb human genomic DNA fragment was isolated, which contained the 3rd exon of the BNP gene and the 1st and 2nd exons of the ANP gene, approximately 8kb apart. Therefore, ANP and BNP genes are organized in tandem in mice and humans.
We examined BNP gene expression in cultured neonatal rat ventricular cardiocytes. During ET-1-induced cardiocyte hypertrophy, BNP mRNA was induced more rapidly t
… More
han ANP mRNA.BNP secretion was also stimulated more rapidly than ANP secretion. Furthermore, BNP mRNA turnover was significantly earlier than ANP mRNA turnover. These results demonstrate that BNP gene expression is distinctly regulated from ANP gene expression at transcriptional and posttranscriptional levels, suggesting the possible role of BNP as an "emergency" cardiac hormone against ventricular overload.
We examined the interaction of endothelial cells (ECs) and vascular smooth muscle cells (SMCs) for endothelial production of CNP and its action on vascular growth. The data indicate augmented production of CNP with the intracellular cGMP accumulation in the EC/SMC coculture. Biologically active TGF-beta in the coculture with direct contact of ECs and SMCs stimulated endothelial productin of CNP.Furthermore, the culture medium from ECs stimulated by TGF-beta had a growth-inhibitory effect on SMCs. These results indicate that endothelial production of CNP in the EC/SMC coculture is at least in part regulated by TGF-beta, suggesting the pathophysiological significance of CNP as a regulator of vascular growth in the interaction of ECs and SMCs. Less
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