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）是全球发病率和死亡率的主要原因。仅在美国，就有近20万名AMI死亡。 AMI是由于冠状动脉缺血（缺乏氧气）和组织死亡的冠状动脉分支的突然血栓性阻塞引起的。 AMI最常见的长期并发症是左心室功能障碍和心力衰竭的晚期。限制心肌损伤的扩展，从而防止心力衰竭迟到仍然是当前的临床挑战。我们最近的创新研究表明，在各种动物和蜂窝模型中，有效的磷酸二酯酶5（PDE-5A）抑制剂在内，包括西地那非柠檬酸盐（伟哥）（伟哥）和vardenafil（Levitra）诱导了针对缺血性再生能力（I/R）的强大心脏保护作用。该应用的目的是进一步证明这些药物对心肌梗塞（MI）诱导的心力衰竭的治疗作用，并开发出创新的方法以实现持久保护。我们将检验以下假设：1）用新型的抑制剂或靶向基因沉默抑制PDE-5A，在体内用慢病毒载体沉默，从而减少了MI-i诱导后的心力衰竭，并通过抑制心脏中心脏肌细胞的抑制，从而减少了MI-i诱导的心力衰竭。 2）。慢性PDE-5A抑制通过增加NO的生物利用度，导致NADPH氧化酶/黄嘌呤氧化酶活性的抑制，抑制了氧化还原敏感的转录因子的激活，从而抑制了NF的激活，从而抑制了NF-从而抑制NF-从而抑制基因表达后，抑制了氧化还原敏感性的转录因子，从而抑制了NADPH氧化酶/黄嘌呤氧化酶活性。 3）CGMP依赖性蛋白激酶（PKGS）的体内基因转移减弱了MI诱导后的重塑和心力衰竭。这些研究将是第一个证明PDE-5A抑制剂和新型的慢病毒基因沉默方法的保护作用，以及MI-i诱导的心力衰竭中相关的信号传导途径。我们预计，这些研究的结果将提供新的见解，以扩大PDE-5A抑制剂对其他心血管指示的实用性，除了当前用于治疗勃起功能障碍和肺动脉高压的临床用途。（pide公共的健康相关性：急性心肌梗死（AMI）仍然是全球发病率和死亡率的主要原因。AMI是由于突然妨碍冠状动脉分支的障碍物引起的，导致心肌缺血（缺氧缺氧）和组织的长期并发症。心脏衰竭。治疗患者的AMI和心室重塑。