Adenylyl cyclase regulation and heart failure

本单元的首要目标是为我们认为可能是治疗心力衰竭的新方法提供一个基本原理和初步测试。在过去的5年里，我们已经证明腺苷酸环化酶（AC）催化剂的表达是β -肾上腺素能受体（β -肾上腺素能受体）激活产生环AMP的关键限制成分。因此，调节Ac的表达是调节心脏反应性的一种合理策略。我们已经测试了AC/VI（哺乳动物心肌细胞中主要的AC异构体）过表达的效用，作为增加心脏对儿茶酚胺刺激的反应性的一种手段。我们已经证明，这种策略是一种非常有效的手段，增加细胞内cAMP和心脏功能，以响应儿茶酚胺刺激。AC的过表达不会改变跨膜信号，除非受体被激活，而受体/G蛋白的过表达则会产生持续的激活和有害的后果。初步实验表明，在心肌病背景下表达AC可改善心功能和肾上腺素能反应性，这些数据表明心脏过表达AC可能是治疗心力衰竭的一种安全有效的手段。我们提出了四个具体目标，每个目标都具有假设检验的性质，如下：1)验证AN/VI表达增加提供相对β -选择性跨膜信号放大的假设；2)验证AC/VI区隔提供β - ar选择性跨膜信号放大的假设；3)验证心脏过表达AC/VI改善小鼠扩张型心肌病心功能和反应性的假说；4)通过大型心力衰竭动物模型，验证心脏过表达AC/VI改善β - aar反应性心功能的假说。

The overriding goal of this Unit is to provide a rationale and an initial test of what we believe may be a new and potentially useful approach for the treatment of heart failure. In the past 5 years we have shown that expression of the catalyst of adenylyl cyclase (AC) is the key limiting component in the generation of cyclic AMP by beta-adrenergic receptor (betaAR) activation. Thus, modulating expression of Ac is a rational strategy for regulating cardiac responsiveness. We have tested the utility of over-expression of AC/VI, a predominant AC isoform in mammalian cardiac myocytes, as a means to increase cardiac responsiveness to catecholamine stimulation. We have demonstrated that this strategy is a highly effective means to increase intracellular cAMP and cardiac function in response to catecholamine stimulation. Over-expressing AC does not alter transmembrane signaling except when receptors are activated, in distinction with receptor/G protein over-expression, which yield continuous activation and the detrimental consequences. Preliminary experiments indicate that expressing AC in the background of cardiomyopathy improves cardiac function and adrenergic responsiveness, These data indicate that cardiac over-expression of AC may be a safe effective means to treat heart failure. We propose four Specific Aims, each of a hypothesis-testing nature, as follows: 1) To test the hypothesis that increased AN/VI expression provides relative betaAR -selective amplification of transmembrane signaling; 2) To test the hypothesis that compartmentation of AC/VI provides betaAR-selective amplification of transmembrane signaling; 3) To test the hypothesis that cardiac over-expression of AC/VI improves cardiac function and responsiveness in murine dilated cardiomyopathy; 4) To test the hypothesis that cardiac over-expression of AC/VI improves cardiac function of betaAR responsiveness in a large animal model of heart failure.