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.

最近，肾上腺外醛固酮合酶系统已被封闭，我们还发现人类衰竭或高血压的心脏也可以合成和分泌醛固酮。我们最近发现ACE抑制剂可以抑制心脏醛固酮的合成。对人类心脏醛固酮的合成进行了更详细的检查。从心力衰竭或非心力衰竭患者的尸检中提取心脏组织，我们检查了 CYP11B2（醛固酮合酶）的基因表达。由于CYP11B2的表达量很小，我们无法通过常规的实时RT-PCR方法检测到它们。然后，我们新修改了实时 RT-PCR，我们能够检测基因表达并对其进行定量。因此，与正常心脏相比，衰竭心脏中CYP11B2的基因表达上调。接下来，利用新生大鼠心肌细胞培养系统检测利尿钠肽（NP）对心脏醛固酮合成的抑制作用。通过GC-A受体拮抗剂HS142-1阻断内源性利钠肽作用，CYP11B2基因显着表达。另外，外源性利钠肽可抑制CYP11B2基因的表达，其剂量是治疗心力衰竭常用的浓度水平。这些结果表明，心脏醛固酮合成受到NP抑制，醛固酮和NP之间的平衡在心力衰竭状态中非常重要。至于醛固酮的病理生理作用，我们最近发现醛固酮增强新生大鼠心肌细胞中ACE基因的表达，使得组织RAAS之间的恶性循环。如上所述，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学意义。在肾素-血管紧张素-醛固酮系统中，不仅血管紧张素II，醛固酮也会直接产生不良作用。刚刚提出了范式转变的方面。