Cardioprotective Signaling following Phosphodiesterase-5 Inhibition

磷酸二酯酶 5 抑制后的心脏保护信号传导

基本信息

批准号：
7867829
负责人：
Rakesh C Kukreja
金额：
$ 37.38万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-14 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7867829
关键词：
Abbreviations Acute myocardial infarction Adenosine Adverse effects Animals Anterior Antioxidants Apoptosis Apoptotic Attenuated Bayer brand of vardenafil hydrochloride Biological Availability Bradykinin Caliber Cardiac Myocytes Cardiomyopathies Cardiovascular system Cell Culture Techniques Cell Death Cell model Cessation of life Chemistry Chronic Cialis Citrates Clinical Clinical Trials Complication Congestive Heart Failure Coronary artery Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cytokine Gene Dose Enzymes Erectile dysfunction Functional disorder GTP-Binding Proteins Gene Expression Gene Silencing Gene Transfer Generations Genes Glycogen Synthase Kinases Guanylate Cyclase Heart Heart Hypertrophy Heart failure Human Immunohistochemistry In Situ Inflammatory Injury Investigation Ischemia Ischemic Preconditioning Knowledge Lead Left Left Ventricular Dysfunction Lentivirus Vector Ligation Mediating Mediator of activation protein Mitochondria Mitogen-Activated Protein Kinases Modeling Molecular Biology Morbidity - disease rate Mus Myocardial Myocardial Infarction Myocardial Ischemia NADPH Oxidase Nitric Oxide Nuclear Obstruction Oligonucleotides Oryctolagus cuniculus Oxidases Oxidation-Reduction Oxidative Stress Oxygen Patients Pharmaceutical Preparations Phosphatidylinositols Phosphorylation Phosphotransferases Physiology Potassium Pulmonary Edema Pulmonary Hypertension Reactive Oxygen Species Reperfusion Therapy Role Signal Pathway Signal Transduction Signal Transduction Pathway Sildenafil citrate Small Interfering RNA Techniques Testing Therapeutic Effect Thick Tissues Ventricular Ventricular Remodeling Viagra Xanthine Oxidase attenuation clinically relevant cytokine in vivo inhibitor/antagonist innovation insight interdisciplinary approach men mitochondrial K(ATP) channel mitochondrial permeability transition pore mortality nitrosative stress novel percutaneous coronary intervention phosphodiesterase V phosphoric diester hydrolase preconditioning prevent protective effect receptor-mediated signaling sildenafil small hairpin RNA tadalafil tool transcription factor vardenafil

项目摘要

DESCRIPTION (provided by applicant): Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Nearly 200,000 patients die yearly of AMI in the US alone. AMI is caused by a sudden thrombotic obstruction to the flow in a coronary artery branch leading to myocardial ischemia (lack of oxygen) and tissue death. The most common long-term complication of AMI is the late occurrence of left ventricular dysfunction and heart failure. Limiting the extension of myocardial damage and thus preventing late occurrence of heart failure remains a current clinical challenge. Our recent innovative studies have demonstrated that potent phosphodiesterase-5 (PDE-5A) inhibitors including sildenafil citrate (Viagra) and vardenafil (Levitra) induce powerful cardioprotective effect against ischemia- reperfusioninjury (I/R) in various animal and cellular models. The purpose of this application is to further demonstrate the therapeutic effect of these drugs against myocardial infarction (MI)-induced heart failure and to develop innovative approaches for long lasting protection. We will test the following hypotheses: 1) Suppression of PDE- 5A with novel class of inhibitors or targeted gene silencing with lentiviral vector in vivo reduce post MI-induced heart failure and attenuate contractile dysfunction via inhibition of cardiomyocyte apoptosis in the heart. 2). Chronic PDE-5A inhibition suppresses oxidative/nitrosative stress by increasing the bioavailability of NO, cause inhibition of NADPH oxidase/xanthine oxidase activity, inhibit activation of redox-sensitive transcription factor, NF- thereby suppressing gene expression of proinflammatory cytokines following MI induced heart failure. 3) In vivo gene transfer of cGMP dependent protein kinases (PKGs) attenuate post MI-induced remodeling and heart failure. These studies will be the first ones to demonstrate the protective effect of PDE-5A inhibitors and novel lentiviral gene silencing approaches and associated signaling pathways in post MI-induced heart failure. We anticipate that results from these investigations will provide novel insights into expanding the utility of the PDE-5A inhibitors for other cardiovascular indications in addition to their current clinical use for treatment of erectile dysfunction and pulmonary hypertension. (PIDEPUBLIC HEALTH RELEVANCE: Acute myocardial infarction (AMI) continues to be a major cause of morbidity and mortality worldwide. AMI is caused by a sudden obstruction to the flow in a coronary artery branch leading to myocardial ischemia (lack of oxygen) and tissue death. The long-term complication of AMI is the late occurrence of left ventricular dysfunction (`weakening of the heart') and heart failure. In this proposal, we will study the effect of erectile dysfunction drugs (Viagra, Levitra and Cialis) and novel gene silencing approaches to limit the damage of the heart following AMI. We believe that knowledge derived from these studies will provide additional tools to the cardiologists for treatment of heart failure with clinically approved erectile dysfunction drugs. In addition, our investigations will open up another innovative gene silencing option to treat AMI and ventricular remodeling in patients.

描述（由申请人提供）：急性心肌梗塞（AMI）是全世界发病和死亡的主要原因。仅在美国，每年就有近 200,000 名患者死于 AMI。 AMI 是由于冠状动脉分支血流突然发生血栓性阻塞，导致心肌缺血（缺氧）和组织死亡而引起的。 AMI 最常见的长期并发症是晚期出现左心室功能障碍和心力衰竭。限制心肌损伤的扩大并从而防止晚期心力衰竭的发生仍然是当前的临床挑战。我们最近的创新研究表明，强效磷酸二酯酶 5 (PDE-5A) 抑制剂，包括柠檬酸西地那非（伟哥）和伐地那非（艾力达），在各种动物和细胞模型中对缺血再灌注损伤 (I/R) 具有强大的心脏保护作用。本申请的目的是进一步证明这些药物对心肌梗死（MI）引起的心力衰竭的治疗效果，并开发长期持久保护的创新方法。我们将测试以下假设：1）用新型抑制剂抑制 PDE-5A 或用慢病毒载体进行体内靶向基因沉默可减少 MI 后诱发的心力衰竭，并通过抑制心脏中的心肌细胞凋亡来减轻收缩功能障碍。 2）。慢性 PDE-5A 抑制通过增加 NO 的生物利用度来抑制氧化/亚硝化应激，抑制 NADPH 氧化酶/黄嘌呤氧化酶活性，抑制氧化还原敏感转录因子 NF- 的激活，从而抑制 MI 诱发的心力衰竭后促炎细胞因子的基因表达。 3) cGMP 依赖性蛋白激酶 (PKG) 的体内基因转移可减弱 MI 后诱导的重塑和心力衰竭。这些研究将首次证明 PDE-5A 抑制剂和新型慢病毒基因沉默方法以及相关信号通路对 MI 后诱发的心力衰竭的保护作用。我们预计，除了目前临床用于治疗勃起功能障碍和肺动脉高压之外，这些研究的结果将为扩大 PDE-5A 抑制剂在其他心血管适应症中的应用提供新的见解。（公众健康相关性：急性心肌梗死 (AMI) 仍然是全世界发病和死亡的主要原因。AMI 是由冠状动脉分支血流突然阻塞导致心肌缺血（缺氧）和组织死亡引起的AMI 的长期并发症是晚期出现左心室功能障碍（“心脏衰弱”）和心力衰竭。在本提案中，我们将研究勃起功能障碍药物的作用。（伟哥、艾力达和希爱力）和限制 AMI 后心脏损伤的新型基因沉默方法，我们相信，从这些研究中获得的知识将为心脏病专家使用临床批准的勃起功能障碍药物治疗心力衰竭提供额外的工具。此外，我们的研究将开辟另一种创新的基因沉默方案来治疗患者的 AMI 和心室重构。