Subtype specific cardiac regulation by adenylyl cyclase and its application for the treatment of heart failure by specific ihhibitor

腺苷酸环化酶亚型特异性心脏调节及其在特异性抑制剂治疗心力衰竭中的应用

基本信息

批准号：
16590719
负责人：
OKUMURA Satoshi
金额：
$ 2.46万
依托单位：
Yokohama City University (2006-2007)Nippon Medical School (2004-2005)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2007
项目状态：
已结题

项目摘要

Desensitization of the cAMP signal is a protective mechanism against catecholamine stress on cardiac myocytes to prevent the development of apoptosis. Molecular mechanisms of desensitization have been well studied at the level of receptors, but poorly at the level of the effector enzyme, adenylyl cyclase. To examine the role of type 5 adenylyl cyclase (AC), a major cardiac isoform, in desensitization and apoptosis, we examined the effects of chronic isoproterenol (ISO) infusion in type 5 adenylyl cyclase-null mice (AC5KO) and wild type controls (WT) Desensitization was more effective in AC5KO after infusion, as reflected by a greater degree of downregulation of AC catalytic activity after infusion. WT showed resistance to such desensitization because the type 5 isoform protein expression underwent paradoxical upregulation. The number of apoptotic myocytes was similar at baseline, but significantly smaller in AC5KO after infusion. This was accompanied by a 4-fold greater increase in Bcl-2 and a 3-fold greater increase in phospho-Akt in AC5KO. The latter is most likely through increased membrane localization of PDK1 (phosphoinositide-dependent protein kinase 1), which is known to be inhibited by the CAMP signal. Thus, the property of AC5KO, i.e., enhanced desensitization and protection against apoptosis, suggests that isoform-specific inhibition of type 5 AC may be beneficial following chronic catecholamine stress, and potentially in the treatment of heart failure.

cAMP信号的脱敏是防止心肌细胞中儿茶酚胺应激的保护机制，以防止凋亡的发展。脱敏的分子机制在受体水平上进行了很好的研究，但在效应酶，腺苷酸环化酶的水平上很差。为了检查5型腺苷酸环化酶（AC）的作用，一种主要的心脏同工型，在脱敏和凋亡中，我们检查了慢性异丙烯醇（ISO）输注在5型腺苷酸腺苷酸（AC5KO）和野生型对照（WT）较大的AC5的AC5中的AC5 KO较大的AC5 KO的影响。输注后的催化活性。 WT表现出对这种脱敏的抗性，因为5型同工蛋白表达进行了矛盾的上调。基线时凋亡肌细胞的数量相似，但输注后AC5KO的数量明显较小。伴随着Bcl-2的增加4倍，AC5KO的磷酸化增加了3倍。后者最有可能是通过增加PDK1的膜定位（磷酸肌醇依赖性蛋白激酶1），该蛋白激酶1）被CAMP信号抑制。因此，AC5KO的特性，即增强的脱敏和对凋亡的保护表明，在慢性儿茶酚胺胁迫下，对5型AC的同工型特异性抑制可能是有益的，并且有可能治疗心力衰竭。