Adenylyl cyclase isoforms in hypertrophy and heart failure

描述(申请人提供)：心力衰竭(HF)在美国仍然是主要的死亡和发病原因。在过去的半个世纪里，HF患者的治疗方法(例如，2-肾上腺素能受体阻滞剂治疗)取得了一些进展，提高了存活率，但幅度不大。由于心力衰竭仍然是该国发病率和死亡率的最主要原因，因此，目前的治疗技术是不够的。这一应用是基于这样一个概念，即对心脏中腺苷酸环化酶(AC)调节的了解的增加将导致新的治疗方法。我们正在验证一种假设，即心脏AC亚型AC5和AC6在心力衰竭的发病机制中表现不同，从而导致抑制AC5可能是治疗心力衰竭的一种新方法。抑制AC5可能优于抑制2-肾上腺素能受体(2-AR)刺激，因为它不损害左心功能，但可能导致更有效的2-AR脱敏。AC5和AC6明显不同的作用是这一应用的基石。假设A：在AC5Tg小鼠中，心脏应激迅速导致LV失代偿、LV肥厚(LVH)和心衰，而AC5KO小鼠则受到保护。AC6TG也被认为是受保护的，但在AC6TG小鼠中，从未研究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AC5 TG相比，AC6 TG对慢性压力超负荷和儿茶酚胺应激有相对的保护作用。假设B：有四种机制可以调节AC5-TG和AC6-TG对压力的反应差异：(1)尽管AC5正常情况下贡献了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，AC5-TG产生的AC活性比AC6-TG更高；(2)AC5和AC6在cAMP的细胞内微域产生差异，该差异受不同亚型的磷酸二酯酶(PDE)调节，如PDE3和PDE4；(3)蛋白质-蛋白质相互作用的差异；以及(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左室失代偿的主要机制。AC5而不是AC6的过表达增加了氧化应激和细胞凋亡，这可以解释AC5KO和AC6TG小鼠对慢性压力超负荷和慢性儿茶酚胺应激反应的差异。对公共卫生的影响是不言而喻的，考虑到心脏病和心力衰竭是对美国公共卫生影响最大的疾病过程，就资金和特别工作组而言，按照类似的逻辑，找到新的治疗方法对于将这些疾病状态对公共卫生的影响降至最低至关重要。公共卫生相关性：在美国，心力衰竭(HF)仍然是导致死亡和发病的主要原因。在过去的半个世纪里，心力衰竭患者的治疗取得了一些进步，提高了存活率，但幅度不大。由于心力衰竭仍然是该国发病率和死亡率的最主要原因，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，考虑到心脏病和心力衰竭是对美国公共卫生影响最大的疾病过程，就资金和特别工作组而言，按照类似的逻辑，找到新的治疗方法对于将这些疾病状态对公共卫生的影响降至最低至关重要。

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.