AC5 Inhibitor Treatment for Heart Failure

AC5 抑制剂治疗心力衰竭

• 批准号: 8010655
• 负责人: STEPHEN F VATNER
• 金额: $ 77.91万
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010655
• 关键词: Adenine; Adenylate Cyclase; Adverse effects; Aging; Applications Grants; Arasena-A; Cardiomyopathies; Cause of Death; Chronic; Clinic; Clinical; Congestive Heart Failure; Conscious; Coronary; Data; Development; Diagnosis; Diet; Disease; Eating; Fatty acid glycerol esters; Genes; Glucose Metabolism Disorders; Goals; Heart failure; Hyperglycemia; Instruction; Investigation; Knockout Mice; Longevity; Marketing; Medicine; Metabolic; Monkeys; Mus; Myocardial; Myocardial Infarction; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Public Health; Screening procedure; Vidarabine; Virus Diseases; Work; adenylyl cyclase type V; base; blood lipid; diabetes control; diabetic; drug efficacy; effective therapy; glucose metabolism; improved; inhibitor/antagonist; instrument; mouse model; preclinical study; pressure; prevent

DESCRIPTION (provided by applicant): Congestive heart failure (HF) in the U.S is the leading cause of death, and the major cause of HF is myocardial ischemic disease. Therefore, improvement of therapy post myocardial infarction (Ml) is extremely important, and the development of a new class of medicine that prevents the progression of HF would have a large market opportunity, representing a significant clinical advance. Additionally, most of these patients have elevated blood lipids and many have impaired glucose metabolism and are either diabetic or pre-diabetic. Therefore, a HF drug which can exert a favorable effect on diabetes control will have a unique niche in the HF market. The goal of this grant proposal is to demonstrate the efficacy of a new class of HF drugs, with a mechanism of inhibition of type 5 adenylyl cyclase (ACS), to improve the adverse effects of remodeling following chronic Ml and to simultaneously improve disorders of glucose metabolism,. This proposal is based on our prior work in a mouse model with disruption of the ACS gene, i.e., ACS knockout mice (ACS KO), and based on the utilization of a specific pharmacological ACS inhibitor. ACS KO mice have prolonged lifespan and are protected from the cardiomyopathy of aging. They are also protected against the development of HF induced by either chronic pressure overload, or by excessive sympathetic stimulation. Another unique feature of the ACS KO mouse model is its ability to increase coronary reserve, which should be particularly useful in preventing the development of HF. Importantly for this proposal these mice eat more than wild type, but weigh less, which points to a favorable metabolic profile, confirmed by our preliminary data using a specific pharmacological ACS inhibitor. In our preliminary screening for ACS inhibitors, adenine 9-?-D-arabinofuranoside (AraAde, also known as Vidarabine or Vira-A(r)), which was used in the clinic for a different indication, i.e., treating viral infections, showed potent and selective inhibition of ACS. Furthermore, our preliminary data demonstrate that the pharmacological AC 5 inhibitor protects against HF following chronic Ml and also protects against development of hyperglycemia induced by a high-fat diet in mice, suggesting that inhibition of ACS improves glucose metabolism in addition to its salutary effects in protecting against HF. Accordingly, in this preclinical study, we will examine the effects of AraAde on post-MI HF with or without impaired glucose metabolism. In addition we will examine the efficacy of this drug in the best pre-clinical model for HF, the chronically instrumented, conscious monkey post-MI. RELEVANCE (See instructions): Almost 5.5 million patients are diagnosed with congestive heart failure in the U.S and the major cause of HF is myocardial ischemic disease. However, no effective therapy has been established to treat congestive HF. The current investigation is aimed at generating a new class of medicine that will prevent progression of HF. Due to the large number of patients with this condition, this may have a significant impact on public health.

描述（由申请人提供）： 在美国，充血性心力衰竭（HF）是导致死亡的主要原因，而心力衰竭的主要原因是心肌缺血性疾病。因此，改善心肌梗塞(MI)后的治疗极其重要，并且开发一类预防心力衰竭进展的新药物将具有巨大的市场机会，代表着重大的临床进步。此外，这些患者大多数血脂升高，许多人葡萄糖代谢受损，并且患有糖尿病或糖尿病前期。因此，能够对糖尿病控制发挥良好作用的心力衰竭药物将在心力衰竭市场上拥有独特的优势。该拨款提案的目标是证明一类新型心力衰竭药物的功效，该药物具有抑制 5 型腺苷酸环化酶 (ACS) 的机制，可改善慢性心肌梗死后重塑的不利影响，同时改善血糖紊乱代谢，。该提议基于我们之前对 ACS 基因破坏的小鼠模型（即 ACS 基因敲除小鼠 (ACS KO)）的研究，并基于特定药理学 ACS 抑制剂的利用。 ACS KO 小鼠的寿命更长，并且可以预防衰老引起的心肌病。它们还可以免受慢性压力超负荷或过度交感神经刺激引起的心力衰竭的影响。 ACS KO 小鼠模型的另一个独特特征是其能够增加冠状动脉储备，这对于预防心力衰竭的发生特别有用。对于这个建议来说重要的是，这些小鼠比野生型小鼠吃得更多，但体重更轻，这表明它们具有良好的代谢特征，我们使用特定药理学 ACS 抑制剂的初步数据证实了这一点。在我们对 ACS 抑制剂的初步筛选中，腺嘌呤 9-β-D-阿拉伯呋喃糖苷（AraAde，也称为阿糖腺苷或 Vira-A(r)）在临床上用于不同的适应症，即治疗病毒感染，显示出有效且选择性地抑制 ACS。此外，我们的初步数据表明，药理学AC 5抑制剂可以预防慢性MI后的心力衰竭，并且还可以预防小鼠中由高脂肪饮食诱导的高血糖的发生，这表明抑制ACS除了在小鼠中具有有益作用外，还可以改善葡萄糖代谢。预防心衰。因此，在这项临床前研究中，我们将研究 AraAde 对有或没有葡萄糖代谢受损的 MI 后心力衰竭的影响。此外，我们将在心衰的最佳临床前模型（长期使用仪器、心梗后有意识的猴子）中检查该药物的疗效。 相关性（参见说明）：在美国，近 550 万患者被诊断患有充血性心力衰竭，心力衰竭的主要原因是心肌缺血性疾病。然而，尚未建立有效的疗法来治疗充血性心力衰竭。目前的研究旨在开发一种新的药物来预防心力衰竭的进展。由于患有这种疾病的患者数量众多，这可能会对公共健康产生重大影响。