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

CAMP信号的脱敏是对抗儿茶酚胺应激对心肌细胞的保护机制，从而阻止细胞凋亡的发展。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-腺苷环化酶水平上的研究很少。为了研究心脏的主要亚型--5型腺酰环化酶(AC)在脱敏和细胞凋亡中的作用，我们观察了长期输注异丙肾上腺素(ISO)对AC5KO小鼠(AC5KO)和野生型对照(WT)在AC5KO中脱敏的影响，反映在输注后AC催化活性的更大程度的下调。WT对这种脱敏表现出抵抗，因为5型异构体蛋白的表达发生了矛盾的上调。基础状态下，AC5KO组的心肌细胞凋亡数相似，但AC5KO组的心肌细胞凋亡数明显减少。伴随而来的是AC5KO中Bcl2增加了4倍，磷酸化Akt增加了3倍。后者很可能是通过增加PDK1(磷脂酰肌醇依赖的蛋白激酶1)的膜定位来实现的，已知该蛋白激酶1被cAMP信号抑制。因此，AC5KO的特性，即增强的脱敏和对细胞凋亡的保护，表明对5型AC的异构体特异性抑制在慢性儿茶酚胺应激后可能是有益的，并有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.