The molecular mechanisms for sympathetic regulation of cardiac function

我们研究了交感神经系统调节心脏功能的分子机制。为此，我们使用了新合成的P-位点抑制物衍生物和转基因小鼠模型，在该模型中，心脏的主要异构体-5型腺酰环化酶的表达被破坏。我们已经进行了计算机辅助的药物筛选，使用了药物核心分析以及分析了酶蛋白和其他化合物的三维结构。类似地，我们研究了交感神经系统对5型腺酰环化酶基因突变小鼠心脏功能的潜在变化。最重要的是，我们发现，通过修饰经典P位点抑制物的侧链，我们可以将它们转化为腺酰环化酶异构体选择性抑制物。特别是，我们发现的其中一种化合物pm6对5型腺酰环化酶异构体的选择性高于其他异构体…。更多的均方根。因此，在存在这种化合物的情况下，心肌细胞的治疗显著地减缓了对儿茶酚胺刺激所致的心肌细胞凋亡的发展。然而，心肌细胞的收缩能力没有受到影响，这表明该化合物可以在不恶化心功能的情况下抑制细胞凋亡的发展。因此，试探性地推测这种化合物可能用于治疗充血性心力衰竭，其中已经使用了β-肾上腺素能阻断治疗。在5型腺酰环化酶基因中断的小鼠中，我们发现交感神经调节在副交感神经调节减弱的基础上减弱。这些发现表明，5型腺酰环化酶不仅在调节交感神经调节方面发挥着重要作用，而且在心脏的副交感神经调节方面也发挥着重要作用。我们还检测了对腺苷酸环化酶阴性小鼠的慢性儿茶酚胺输注的影响。我们发现，在基因敲除的小鼠中，心肌细胞凋亡的发展也显著减弱。较少

We have investigated the molecular mechanisms for the regulation of cardiac function by the sympathetic nervous system. For this purpose, we have used newly synthesized P-site inhibitor derivatives and transgenic mouse model in which the expression of type 5 adenylyl cyclase, the major cardiac isoform, is disrupted. We have conducted computer-assisted, drug screening by the use of pharma-core analysis as well as the analysis of the 3D structure of the enzyme protein and miscellaneous compounds. Similarly, we have examined potential changes in cardiac function and the regulation by the sympathetic nervous system in mice with the disrupted type 5 adenylyl cyclase gene.Most importantly, we have found that by modifying the side chains of classical P-site inhibitors, we can convert them into an adenylyl cyclase isoform-selective inhibitor. In particular, PM6, one of such compounds we have discovered, has demonstrated a high selectivity to the type 5 adenylyl cyclase isoform over other isofo … More rms. Accordingly, the treatment of cardiac myocytes in the presence of this compound significantly attenuated the development of cardiac myocyte apoptosis in response to prolonged catecholamine stimulation. Cardiac myocyte contractility was, however, unaffected, suggesting that this compound can inhibit the development of apoptosis without deteriorating cardiac function. It is thus tentative to speculate that such compound may be useful in the treatment of congestive heart failure, in which beta-adrenergic blockade therapy has been used.In mice with disrupted type 5 adenylyl cyclase gene, we have found that sympathetic regulation is attenuated on the top of diminished parasympathetic regulation. These findings suggest that type 5 adenylyl cyclase plays a major role in not only regulating sympathetic regulation, but parasympathetic regulation of the heart. We have also examined the effect of chronic catecholamine infusion in adenylyl cyclase-null mice. We have found that the development of cardiac myocyte apoptosis was significantly attenuated in knockout mice as well. Less