Rescue of Beta-Adrenergic Cardiomyopathy by Inhibition of Adenylyl Cyclase

通过抑制腺苷酸环化酶来挽救β-肾上腺素能心肌病

• 批准号: 7787533
• 负责人: Dorothy Eileen Vatner
• 金额: $ 39万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-16 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787533
• 关键词: Adenylate Cyclase; Adrenergic Agents; Adrenergic Receptor; Adverse effects; Advisory Committees; Age; Antioxidants; Arts; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiomyopathies; Catecholamines; Cell Death; Chronic; Clinical; Clinical Research; Complement component C1s; Complex; Coronary; Disease; Enzymes; Exercise; Exercise Tolerance; Exhibits; Goals; Heart; Heart Diseases; Heart Rate; Heart failure; Human; Inhibition of Apoptosis; Knock-out; Knockout Mice; Laboratories; Logic; Longevity; Manganese Superoxide Dismutase; Mediating; Modeling; Mus; Muscle Cells; Nitric Oxide; Oxidative Stress; Oxygen Consumption; Partner in relationship; Pathogenesis; Patients; Performance; Physiological; Play; Process; Production; Public Health; Receptor Signaling; Resistance; Role; Signal Transduction; Signaling Molecule; Source; Stress; Stroke Volume; Sympathetic Nervous System; Techniques; Therapeutic; Transgenic Organisms; adenylyl cyclase type V; adrenergic; improved; inhibitor/antagonist; novel; novel therapeutic intervention; overexpression; oxidative DNA damage; pressure; public health relevance; public health research; research study; response

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.

描述（由申请人提供）：交感神经系统与心力衰竭（HF）的发病机制密切相关。目前，临床研究充分认识到抑制交感神经活性对HF有益。尽管这种方法现在在临床上是常规的，但是这种在<$-肾上腺素能受体（<$-AR）水平上抑制交感神经活性的治疗方法在一些HF患者中的有用性存在一些限制。本项目的总体目标是探索在腺苷酸环化酶（AC）水平抑制<$-AR的作用，并研究HF的潜在新治疗方法，即，抑制5型腺苷酸环化酶（AC 5）。我们的总体假设是，AC 5是介导心肌病的关键酶，其响应于心脏超负荷，其次是响应于<$1-AR或<$2-AR过表达的小鼠中<$1-AR信号的增加或由<$1-AR或<$2-AR信号的慢性增强诱导的心肌病，并且AC 5的抑制挽救了这些转基因（Tg）小鼠中的心肌病。人们可能会认为，减少AC活性本身将负责挽救AR心肌病。然而，心脏中AC活性的主要来源是AC 6，并且，由于我们已经证明AC 5 KO仅表现出AC活性的25-30%降低，因此对<$2-AR Tg心肌病的挽救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AC 5来挽救心肌病的潜在机制，这将支持该分子作为HF的新型治疗的临床用途。有三个主要的假设：假设A：AC 5的抑制可以防止细胞死亡并挽救由过表达的<$1-AR或<$2-AR诱导的心肌病。假设B：拯救世界1-AR Tg或？通过抑制AC 5治疗2-AR Tg心肌病允许增强的运动表现，这是由于（1）改善的心输出量和每搏输出量，（2）改善的冠状动脉储备，和（3）增强的一氧化氮（NO）信号传导。假设C：在<$1-AR Tg x AC 5敲除（KO）或<$2-AR Tg x AC 5 KO双基因小鼠中，抗氧化应激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。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。