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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 信号脱敏是一种针对心肌细胞儿茶酚胺应激的保护机制，可防止细胞凋亡的发生。脱敏的分子机制在受体水平上已得到充分研究，但在效应酶腺苷酸环化酶水平上的研究却很少。为了研究主要心脏同工型 5 型腺苷酸环化酶 (AC) 在脱敏和细胞凋亡中的作用，我们研究了长期输注异丙肾上腺素 (ISO) 对 5 型腺苷酸环化酶缺失小鼠 (AC5KO) 和野生型对照 (WT) 的影响。输注后的催化活性。 WT 对这种脱敏表现出抵抗力，因为 5 型亚型蛋白表达经历了矛盾的上调。基线时凋亡肌细胞的数量相似，但输注后 AC5KO 中的凋亡肌细胞数量明显减少。 AC5KO 中，Bcl-2 增加了 4 倍，磷酸 Akt 增加了 3 倍。后者很可能是通过增加 PDK1（磷酸肌醇依赖性蛋白激酶 1）的膜定位来实现的，已知 PDK1 会受到 CAMP 信号的抑制。因此，AC5KO 的特性，即增强脱敏和防止细胞凋亡，表明 5 型 AC 的异构体特异性抑制可能在慢性儿茶酚胺应激后有益，并且可能有助于治疗心力衰竭。