Pathosignificance of cardiac aldosterone synthesis in heart failure

近年来，肾上腺外的醛固酮合成酶系统已被关闭，我们还发现，醛固酮的合成和分泌来自于人类衰竭或高血压心脏。我们最近发现心脏的醛固酮合成被血管紧张素转换酶抑制剂抑制。更详细的研究是关于人类心脏的醛固酮合成。从心力衰竭和非心力衰竭患者的尸检中提取心脏组织，检测CYP11B2、醛固酮合成酶的基因表达。由于细胞色素P11B2的表达水平很低，用常规的实时荧光RT-PCR方法无法检测到。然后，我们对实时荧光RT-PCR进行了改进，能够检测到基因的表达并对其进行量化。接下来，利用新生大鼠心肌细胞培养系统检测了钠尿肽(NP)对心脏醛固酮合成的抑制作用。用GC-A受体拮抗剂HS142-1阻断内源性利钠肽作用后，细胞色素P11B2基因显著表达。此外，外源性利钠肽抑制了CYP11B2基因的表达，其剂量是治疗心力衰竭的常用浓度水平。这些结果表明，心脏醛固酮的合成受到NP的抑制，在心力衰竭状态下，醛固酮和NP之间的平衡将是非常重要的。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中ACE基因的表达，使组织之间的RAAS之间发生了恶性循环。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作用。范式转变的方面刚刚呈现出来。

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.