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Pathosignificance of cardiac aldosterone synthesis in heart failure

心脏醛固酮合成在心力衰竭中的病理意义

基本信息

批准号：
13670729
负责人：
YOSHIMURA Michihiro
金额：
$ 2.05万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Extra-adrenal aldosterone synthase system has been closed-up recently and we also showed that aldosterone was synthesized and secreted from human failing or hypertensive heart. And we recently showed that cardiac aldosterone synthesis is suppressed by ACE inhibitor.Still more detailed examination was performed about the human cardiac aldosterone synthesis. The cardiac tissue was extracted from the autopsy of patients with heart failure or non-heart failure and we examined gene expression of CYP11B2, aldosterone synthase. Since the expression of CYP11B2 was very small, we could not detect them by usual real-time RT-PCR method. Then, we newly modified real-time RT-PCR and we were able to detect the gene expression and quantified them. Consequently, the gene expression of CYP11B2 was up-regulated in the failing heart compared with the non-failing heart.Next, the inhibitory effect of natriuretic peptide (NP) on cardiac aldosterone synthesis was examined using neonatal rat cardiocyte culture system. By blocking endogenous natriuretic peptide effect with HS142-1, a GC-A receptor antagonist, CYP11B2 gene was significantly expressed. Also, exogenous natriuretic peptide suppressed the CYP11B2 gene expression, the dose of which was a commonly used concentration level in the treatment of heart failure. These results indicate that cardiac aldosterone synthesis is suppressed by NP and the balancing between aldosterone and NP would be very important in heart failure status.As for pathophysiological roles of aldosterone, we recently found that aldosterone augments the ACE gene expression in neonatal rat cardiocytes, making a vicious cycle between tissue RAAS.As mentioned above, we have studied about cardiac aldosterone synthesis and its pathophysiological significance in heart failure. In he renin-angiotensin-aldosterone system, not only angiotensin II but also aldosterone would provide unfavorable effects directly. The aspect of a paradigm shift has just been presented.

近年来，肾上腺外醛固酮合成酶系统已被关闭，我们也发现在人类衰竭或高血压心脏中合成和分泌醛固酮。我们最近发现心脏醛固酮合成被ACE抑制剂抑制，对人心脏醛固酮合成进行了更详细的研究。从心力衰竭或非心力衰竭患者的尸检中提取心脏组织，我们检测了CYP 11B 2、醛固酮合酶的基因表达。由于CYP 11B 2的表达量很小，不能用常规的实时荧光定量PCR方法检测。然后，我们新修改的实时RT-PCR，我们能够检测基因表达和定量。因此，与非衰竭心脏相比，衰竭心脏中CYP 11B 2基因表达上调。其次，利用新生大鼠心肌细胞培养系统，检测利钠肽（NP）对心脏醛固酮合成的抑制作用。用GC-A受体拮抗剂HS 142 -1阻断内源性利钠肽的作用，使CYP 11B 2基因显著表达。此外，外源性利钠肽抑制CYP 11B 2基因表达，其剂量是心力衰竭治疗中常用的浓度水平。这些结果表明，心脏醛固酮合成受到NP的抑制，醛固酮与NP之间的平衡在心力衰竭状态中是非常重要的。至于醛固酮的病理生理作用，我们最近发现，醛固酮增加了新生大鼠心肌细胞ACE基因的表达，使组织RAAS之间形成恶性循环。我们研究了心脏醛固酮的合成及其在心力衰竭中的病理生理意义。在肾素-血管紧张素-醛固酮系统中，不仅血管紧张素II而且醛固酮也会直接产生不利影响。范式转变的方面刚刚被提出。