Cardioprotective Signaling following Phosphodiesterase-5 Inhibition

项目说明 急性心肌梗死是世界范围内发病率和死亡率的主要原因。 仅在美国，每年就有近20万患者死于急性心肌梗死。急性心肌梗死是由突如其来的 血栓性冠状动脉分支血流阻塞导致心肌梗死 缺血(缺氧)和组织死亡。最常见的长期并发症 急性心肌梗死的主要原因是晚期发生左心功能不全和心力衰竭。限制 延长心肌损伤，从而防止心力衰竭的晚期发生 仍然是目前临床上的一个挑战。我们最近的创新研究表明 包括柠檬酸西地那非(伟哥)在内的有效磷酸二酯酶-5(PDE-5A)抑制剂 和伐地那非(Levitra)可诱导强大的抗缺血心脏保护作用。 各种动物和细胞模型的再灌注损伤(I/R)。这样做的目的是 应用是为了进一步证明这些药物的治疗效果 心肌梗死(MI)导致的心力衰竭并开发创新的治疗方法 持久的保护。我们将检验以下假设：1)抑制PDE- 5A与新型抑制剂或慢病毒载体靶向基因沉默 活体减少心肌梗死后心力衰竭并减轻收缩功能障碍 通过抑制心脏中的心肌细胞凋亡。2)。慢性PDE-5A 抑制通过提高生物利用度抑制氧化/亚硝化应激 对NO，引起NADPH氧化酶/黄嘌呤氧化酶活性抑制，抑制 氧化还原敏感转录因子-核因子的激活，从而抑制 心肌梗死心衰后促炎细胞因子的基因表达。 3)体内基因转移后cGMP依赖的蛋白激酶(PKG)减弱 心肌梗死诱发的重塑和心力衰竭。这些研究将是第一批 展示PDE-5A抑制剂的保护作用和新型慢病毒基因沉默 心肌梗死后心力衰竭的治疗途径和相关信号通路。我们 预计这些调查结果将为扩展业务提供新的见解 PDE-5A抑制剂在其他心血管适应症中的应用 目前临床用于治疗勃起功能障碍和肺动脉高压。平实叙事 急性心肌梗死(AMI)仍然是发病率和死亡率的主要原因 全球范围内的死亡率。急性心肌梗死是由于冠状动脉血流突然受阻所致。 动脉分支导致心肌缺血(缺氧)和组织死亡。这个 急性心肌梗死的长期并发症是左心功能不全的晚期发生 (‘心脏衰弱’)和心力衰竭。在这项建议中，我们将研究 勃起功能障碍药物(伟哥、利维特拉和喜力士)与新的基因沉默 限制急性心肌梗死后心脏损害的方法。我们相信这一知识 这些研究的结果将为心脏病专家提供更多的治疗工具 用临床批准的勃起功能障碍药物治疗心力衰竭。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急性心肌梗塞和 患者的室壁重塑。

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.