Adenylyl cyclase isoforms in hypertrophy and heart failure

描述（由申请人提供）：心力衰竭（HF）在美国仍然是死亡率和发病率的主要原因。在过去的半个世纪，在治疗HF患者方面取得了一些进展（例如，2-肾上腺素能受体阻断疗法）改善了存活率，但仅是适度的。由于HF仍然是该国发病率和死亡率最突出的原因，因此目前的治疗技术是不够的。该应用基于这样的概念，即增加对心脏中腺苷酸环化酶（AC）调节的理解将导致新的治疗方法。我们正在验证心脏AC亚型AC 5和AC 6在HF发病机制中表现不同的假设，这导致抑制AC 5可能是治疗HF的新方法。抑制AC 5可能上级于抑制2-肾上腺素能受体（2-AR）刺激，因为它不损害左心室（LV）功能，但可能导致更有效的2-AR脱敏。AC 5和AC 6明显不同的动作是该应用程序的基石。有3个主要假设：假设A：在AC 5 Tg小鼠中，心脏应激迅速导致LV失代偿、LV肥大（LVH）和HF，而AC 5 KO小鼠受到保护。AC 6 Tg也被认为是受保护的，但在AC 6 Tg小鼠中从未检查过慢性压力超负荷和慢性儿茶酚胺应激的影响。我们的假设是，与AC 5 Tg相比，AC 6 Tg相对于慢性压力超负荷和儿茶酚胺应激具有保护作用。假设B：有四种机制可以调和AC 5 Tg和AC 6 Tg在响应胁迫方面的差异：（1）虽然AC 5通常贡献大约三分之一的环化酶活性，但对于给定的转基因表达增加，AC 5 Tg比AC 6 Tg产生更多的AC活性;（2）AC 5和AC 6在cAMP的胞内微区产生差异，其受磷酸二酯酶（PDE）的不同亚型调节，例如PDE 3和PDE 4;（3）蛋白质-蛋白质相互作用的差异;和（4）细胞内定位的差异。假设C：氧化应激是慢性压力超负荷或儿茶酚胺应激诱导细胞凋亡和LV失代偿的主要机制。AC 5的过表达，而不是AC 6，增加氧化应激和细胞凋亡，这可以解释AC 5 KO和AC 6 Tg小鼠对慢性压力超负荷和慢性儿茶酚胺应激反应的差异。考虑到心脏病和HF是对美国公共卫生影响最大的疾病过程，在财务和工作组方面，对公共卫生的影响不言而喻，并且使用类似的逻辑，找到新的治疗方法对于最大限度地减少这些疾病状态对公共卫生的影响至关重要。公共卫生相关性：在美国，心力衰竭（HF）仍然是死亡率和发病率的主要原因。在过去的半个世纪中，HF患者治疗的一些进展改善了存活率，但仅是适度的。由于HF仍然是该国发病率和死亡率最突出的原因，因此目前的治疗技术是不够的。对公共卫生的影响是不言而喻的，考虑到心脏病和HF是对美国公共卫生影响最大的疾病过程，就财政和工作组而言，并使用类似的逻辑，寻找新的治疗方法对于最大限度地减少这些疾病状态对公共卫生的影响至关重要。

DESCRIPTION (provided by applicant): Heart failure (HF) remains pre-eminent as a cause of mortality and morbidity in the U.S. Over the past half century several advances in the treatment of patients with HF (e.g., 2-adrenergic receptor blockade therapy) have improved survival, but only modestly. Since HF remains the most prominent cause of morbidity and mortality in this country, it follows that current therapeutic techniques are not adequate. This application is based on the concept that an increased understanding of adenylyl cyclase (AC) regulation in the heart will lead to novel therapeutic approaches. We are testing the hypothesis that the cardiac AC isoforms, AC5 and AC6, behave differently in the pathogenesis of HF leading to the concept that inhibition of AC5 may be a novel approach to the treatment of HF. Inhibition of AC5 may be superior to inhibition of 2-adrenergic receptor (2-AR) stimulation, since it does not impair left ventricular (LV) function, yet may lead to more effective 2-AR desensitization. The apparent different actions of AC5 and AC6 are the cornerstones of this application. There are 3 major hypotheses: Hypothesis A: In the AC5 Tg mice, cardiac stress leads rapidly to LV decompensation, LV hypertrophy (LVH), and HF, whereas AC5 KO mice are protected. AC6 Tg are also thought to be protected, but the effects of chronic pressure overload and chronic catecholamine stress have never been examined in AC6 Tg mice. Our hypothesis is that AC6 Tg are relatively protected from chronic pressure overload and catecholamine stress compared with AC5 Tg. Hypothesis B: There are four mechanisms, which can reconcile the differences between AC5 Tg and AC6 Tg in response to stress (1) Although AC5 contributes roughly a third of cyclase activity normally, the AC5 Tg generates more AC activity than AC6 Tg for a given increase in transgene expression; (2) AC5 and AC6 generate differences in intracellular microdomains of cAMP, which are regulated by different subtypes of phosphodiesterase (PDE), e.g. PDE3 and PDE4; (3) differences in protein-protein interactions; and (4) differences in intracellular localizations. Hypothesis C: Oxidative stress is a major mechanism by which chronic pressure overload or catecholamine stress induces apoptosis and LV decompensation. Overexpression of AC5, but not AC6, increases oxidative stress and apoptosis, which can explain the differences in response to chronic pressure overload and chronic catecholamine stress in AC5 KO and AC6 Tg mice. The implications for Public Health are self-evident, considering that heart disease and HF are the disease processes which have the greatest impact on Public Health in the US, in terms of finances and task- force, and using similar logic, finding new therapies will be crucial to minimize the impact of these disease states on Public Health. PUBLIC HEALTH RELEVANCE: Heart failure (HF) remains pre-eminent as a cause of mortality and morbidity in the U.S. Over the past half century several advances in the treatment of patients with HF have improved survival, but only modestly. Since HF remains the most prominent cause of morbidity and mortality in this country, it follows that current therapeutic techniques are not adequate. The implications for Public Health are self-evident, considering that heart disease and HF are the disease processes which have the greatest impact on Public Health in the US, in terms of finances and task-force, and using similar logic, finding new therapies will be crucial to minimize the impact of these disease states on Public Health.