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

cAMP信号脱敏是心肌细胞抗儿茶酚胺应激、防止细胞凋亡的保护机制。脱敏的分子机制已经在受体水平上得到了很好的研究，但在效应酶腺苷酸环化酶水平上的研究很少。为了研究5型腺苷酸环化酶（AC）在脱敏和凋亡中的作用，我们研究了慢性异丙肾上腺素（ISO）输注对5型腺苷酸环化酶缺失小鼠（AC5KO）和野生型对照组（WT）的影响。输注后AC5KO脱敏效果更明显，这反映在输注后AC催化活性的更大程度下调。WT表现出对这种脱敏的抗性，因为5型异构体蛋白的表达经历了矛盾的上调。在AC5KO输注后，凋亡的肌细胞数量在基线时相似，但明显减少。与此同时，AC5KO中Bcl-2增加了4倍，phospho-Akt增加了3倍。后者最有可能是通过增加PDK1（磷酸肌醇依赖性蛋白激酶1）的膜定位，已知PDK1可被CAMP信号抑制。因此，AC5KO的特性，即增强脱敏和保护细胞凋亡，表明对5型AC的异型特异性抑制可能对慢性儿茶酚胺应激有益，并可能用于心力衰竭的治疗。

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.