Adenylyl cyclase regulation and heart failure

这个单位的首要目标是为我们认为可能是治疗心力衰竭的一种新的和潜在有用的方法提供一个理论基础和初步测试。在过去的5年中，我们已经证明腺苷环化酶(AC)催化剂的表达是β-肾上腺素能受体(BetaAR)激活产生环状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合理策略。我们已经测试了在哺乳动物心肌细胞中过表达AC/VI作为增加心脏对儿茶酚胺刺激的反应性的一种手段的效用。我们已经证明，这种策略是对儿茶酚胺刺激反应增加细胞内cAMP和心功能的一种非常有效的手段。AC的过度表达不会改变跨膜信号，除非受体被激活，这与受体/G蛋白的过度表达不同，后者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，提示心脏过度表达AC可能是治疗心力衰竭的一种安全有效的手段。我们提出了四个特定的目标，每个目标都具有假设检验的性质，如下：1)检验假设，即增加的AN/VI表达提供相对的跨膜信号的βAR选择性放大；2)检验AC/VI的区隔提供βAR选择性放大跨膜信号的假设；3)检验AC/VI心脏过度表达改善扩张型心肌病小鼠心功能和反应性的假设；4)在大型动物心力衰竭模型中检验AC/VI心脏过度表达改善心功能βAR反应性的假设。

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.