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：
8258744
负责人：
Rakesh C Kukreja
金额：
$ 37万
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/8258744
关键词：
Abbreviations Acute myocardial infarction Adenosine Adverse effects Animal Model 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 Production Protein Isoforms Pulmonary Edema Pulmonary Hypertension Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Role Signal Pathway Signal Transduction Signal Transduction Pathway Sildenafil citrate Small Interfering RNA TNF gene Techniques Testing Therapeutic Therapeutic Effect Thick Tissues Ventricular Ventricular Remodeling Viagra Xanthine Oxidase attenuation clinically relevant cytokine improved 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

Project Description 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. LAY NARRATIVE 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.

项目描述急性心肌梗塞（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突然引起冠状动脉分支流动的血栓性阻塞导致心肌缺血（缺氧）和组织死亡。最常见的长期并发症 AMI是左心室功能障碍和心力衰竭的晚期。限制心肌损伤的延伸，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有效的磷酸二酯酶5（PDE-5A）抑制剂，包括柠檬酸西地那非（伟哥） Vardenafil（Levitra）对缺血 - 各种动物和细胞模型中的再灌注（I/R）。这个目的应用是进一步证明这些药物对心肌梗死（MI）引起的心力衰竭并开发创新方法持久的保护。我们将测试以下假设：1）抑制PDE- 5A具有新型抑制剂或靶向基因沉默，并用慢病毒载体沉默体内减少MI诱导的心力衰竭并减轻收缩功能障碍通过抑制心脏中心肌细胞凋亡。 2）。慢性PDE-5A 抑制通过增加生物利用度来抑制氧化/硝化应激否，导致抑制NADPH氧化酶/黄嘌呤氧化酶活性，抑制激活氧化还原敏感的转录因子，从而抑制 MI诱导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（PKGS）的体内基因转移 MI诱导的重塑和心力衰竭。这些研究将是第一个证明PDE-5A抑制剂和新型慢病毒基因沉默的保护作用 MI后诱导的心力衰竭的接近和相关信号通路。我们预计这些调查的结果将为扩展提供新颖的见解 PDE-5A抑制剂对其他心血管指示的效用当前用于治疗勃起功能障碍和肺动脉高压的临床用途。叙述急性心肌梗塞（AMI）仍然是发病率和全球死亡率。 AMI是由于冠状动脉中的流动突然阻塞引起的动脉分支导致心肌缺血（缺乏氧）和组织死亡。这 AMI的长期并发症是左心室功能障碍的晚期。（“心脏削弱”）和心力衰竭。在此提案中，我们将研究勃起功能障碍药物（伟哥，levitra和cialis）和新型基因沉默 AMI之后，限制心脏损害的方法。我们相信知识从这些研究中得出的将为心脏病学家提供其他工具进行治疗临床批准的勃起功能障碍药物的心力衰竭。另外，我们的调查将为治疗AMI和患者的心室重塑。