Rescue of Beta-Adrenergic Cardiomyopathy by Inhibition of Adenylyl Cyclase

描述(由申请人提供)：交感神经系统在心力衰竭(HF)的发病机制中起关键作用。目前，临床研究已经很好地认识到抑制交感神经活动对心衰是有益的。虽然这种方法现在是临床上的常规方法，但这种在肾上腺素能受体(？-AR)水平上抑制交感神经活动的治疗方法在某些心力衰竭患者中的有效性存在一些限制。本项目的总体目标是探索在腺酰环化酶(AC)水平上抑制β-AR的作用，并研究一种潜在的治疗HF的新方法，即抑制5型腺酰环化酶(AC5)。我们的总体假设是，AC5是一种关键的酶，在1-AR或2-AR过度表达的小鼠中，AC5是介导心肌病的关键酶，继而是β-AR信号的增加或由于β-AR信号的长期增强而引起的心肌病，抑制AC5可以挽救这些转基因(TG)小鼠的心肌病。人们可能会认为，减少AC活动本身就是拯救非AR心肌病的原因。然而，心脏中AC活性的主要来源是AC6，由于我们已经证明AC5 KO仅显示AC活性降低25%-30%，拯救2-AR TG心肌病必须涉及复杂的机制相互作用，而不仅仅是由于AC活性的适度降低。该项目的目标是确定通过抑制AC5来挽救心肌病的潜在机制，这将支持该分子作为一种新的治疗心力衰竭的临床应用。有三个主要的假设：假设A：抑制AC5可以保护细胞免于死亡，并挽救由过度表达的1-AR或2-AR引起的心肌病。假设B：通过抑制AC5来挽救1-AR TG或2-AR TG心肌病可以增强运动能力，这是由于(1)心输出量和每搏量增加，(2)冠状动脉储备增加，以及(3)一氧化氮(NO)信号增强。假设C：在1-AR Tg x AC5基因敲除(KO)或2-AR Tg x AC5 KO双基因敲除小鼠中，对氧化应激的抵抗是防止细胞死亡和挽救心肌病的重要机制。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：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): The sympathetic nervous system is critically involved in the pathogenesis of heart failure (HF). It is now currently well recognized from clinical studies that inhibiting sympathetic activity is salutary in HF. Whereas this approach is now routine clinically there are some limitations to the usefulness of this therapeutic approach of inhibiting sympathetic activity at the level of ¿-adrenergic receptors (¿-AR) in some patients with HF. The overall goal of this project is to explore the role of inhibiting ¿-AR at the level of adenylyl cyclase (AC) and to study a potentially new therapeutic approach for HF, i.e., inhibition of type 5 adenylyl cyclase (AC5). Our overall hypothesis is that AC5 is a key enzyme mediating cardiomyopathy in response to cardiac overload and secondarily to increased ¿-AR signaling or to cardiomyopathy induced by chronically enhanced ¿-AR signaling in mice with overexpressed ¿1-AR or ¿2-AR and that inhibition of AC5 rescues the cardiomyopathy in these transgenic (Tg) mice. One might suppose that reducing AC activity will, by itself, be responsible for rescuing ¿-AR cardiomyopathy. However, the main source of AC activity in the heart is AC6, and, since we have demonstrated that AC5 KO only exhibit a 25-30% reduction in AC activity, the rescue of ¿2-AR Tg cardiomyopathy must involve a complex interaction of mechanisms, not simply due to the modest decrease in AC activity. The goal of this project is to determine the mechanisms underlying rescue of cardiomyopathy by inhibition of AC5, which will support the clinical use of this molecule as a novel treatment for HF. There are three major hypotheses: Hypothesis A: Inhibition of AC5 protects against cell death and rescues the cardiomyopathy induced by overexpressed ¿1-AR or ¿2-AR. Hypothesis B: The rescue of the ¿1-AR Tg or ¿2-AR Tg cardiomyopathies by inhibition of AC5 permits enhanced exercise performance which is due to (1) improved cardiac output and stroke volume, (2) improved coronary reserve, and (3) enhanced nitric oxide (NO) signaling. Hypothesis C: Resistance to oxidative stress is an important mechanism in the protection against cell death and rescue of cardiomyopathy in ¿1-AR Tg x AC5 knockout (KO) or ¿2-AR Tg x AC5 KO bigenic 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: 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.