Molecular and Clinical Study of Cardiovascular Hormones

心血管激素的分子和临床研究

• 批准号: 08044272
• 负责人: NAKAO Kazuwa
• 金额: $ 4.8万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08044272/
• 关键词: Natriuretic peptide; Endothelin; Angiotensin receptor; Cardiovascular hormone; Molecular biology; Knockout mouse; Transgenic mouse; Gene transfer

Recent studies have shown that novel' cardiovascular hormones' may be implicated in various cardiovascular disorders such as hypertension and myocardial infarction. To further explore their roles, we studied the natriuretic peptide system, endothelin system, and renin-angiotensin system at the molecular level in clinical and experimental settings, including genetically engineered animal models.Endothelial production of C-type natriuretic peptide (CNP), possessing vasorelaxant and antiproliferative properties, was markedly increased through TGF-BETA activation under coculture with vascular smooth muscle cells (VSVC), and was significantly decreased by vascular endothelial growth factor or insulin. Furthermore, the G1 arrest was induced by adenovirus-mediated CNP gene transfer into VSMC,and CNP induced an antiproliferative homeobox Gax as opposed to the effect of angiotensinII.Thus, these Multiple mediators may be interacting locally in vascular remodeling, being potential targets for ca … More rdiovacular gene therapy. We also showed that transgenic mice overexpressing brain natriuretic peptide(BNP) exhibited significant hypotension with decreased cardiac mass, suggesting its cardioprotective effect. We further revealed that the BNP and ANP genes are organized in tandem in the mouse and humangenomes.We also revealed the presence of short nonfunctional forms of the endothelin-A receptor in various human tissues by alternative RNA splicing, suggesting a regulatory role in its gene expression.Angiotensin II type 2(AT_2) receptor was abundantly expressed in human myometrium and markedly down-regulated during pregnancy, suggesting its role in uterine function. In cultured rat mesangial cells, the AT_2 receptor was markedly induced upon confluency and exerted an antiproliferative effect, counteracting the AT_1 receptor. Lower expression of the AT_2 receptor in genetically hypertensive rat kidneys suggested its implication in pathogenesis of hypertension. Furthermore, in hypertensive transgenic rats overexpressing mouse renin (Ren-2), cardiac secretion of ANP and BNP upon stimulation was attenuated, suggesting its contribution to their cardiovascular complications. Less

最近的研究表明，新的“心血管激素”可能与高血压和心肌梗死等各种心血管疾病有关。为了进一步探索它们的作用，我们在临床和实验环境下，包括基因工程动物模型，研究了利钠肽系统、内皮素系统和肾素-血管紧张素系统的分子水平。具有血管松弛和抗增殖特性的c型利钠肽（CNP）在与血管平滑肌细胞（VSVC）共培养时，通过tgf - β激活可显著增加内皮细胞的生成，而血管内皮生长因子或胰岛素可显著降低其生成。此外，腺病毒介导的CNP基因转移到VSMC诱导G1阻滞，CNP诱导抗增殖同源盒Gax，而不是血管紧张素i的作用。因此，这些多种介质可能在局部血管重构中相互作用，成为更多放射性基因治疗的潜在靶点。我们还发现，过表达脑利钠肽（BNP）的转基因小鼠表现出明显的低血压和心脏质量下降，表明其具有心脏保护作用。我们进一步揭示了BNP和ANP基因在小鼠和人类基因组中串联组织。我们还发现，通过选择性RNA剪接，内皮素a受体在多种人体组织中存在短的无功能形式，这表明其基因表达具有调节作用。血管紧张素II型2（Angiotensin II type 2, AT_2）受体在人子宫肌层中大量表达，并在妊娠期显著下调，提示其在子宫功能中的作用。在培养的大鼠系膜细胞中，AT_2受体被明显诱导融合，并发挥抗增殖作用，抵消AT_1受体。遗传性高血压大鼠肾脏中AT_2受体的低表达提示其与高血压的发病机制有关。此外，在过表达小鼠肾素（Ren-2）的高血压转基因大鼠中，刺激后心脏分泌的ANP和BNP减少，提示其与心血管并发症有关。少

项目成果

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