Cardioprotective Signaling following Phosphodiesterase-5 Inhibition

描述（由申请人提供）：急性心肌梗死（AMI）是全球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AMI。急性心肌梗死是由冠状动脉分支中的流动的突然血栓性阻塞引起的，导致心肌缺血（缺氧）和组织死亡。AMI最常见的远期并发症是晚期发生的左心室功能不全和心力衰竭。限制心肌损伤的扩展，从而防止心力衰竭的晚期发生仍然是当前的临床挑战。我们最近的创新性研究表明，有效的磷酸二酯酶-5（PDE-5A）抑制剂包括枸橼酸西地那非（万艾可）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）诱导的心力衰竭的治疗效果，并开发持久保护的创新方法。我们将测试以下假设：1）在体内用新型抑制剂抑制PDE- 5A或用慢病毒载体靶向基因沉默减少MI后诱导的心力衰竭，并通过抑制心脏中的心肌细胞凋亡减轻收缩功能障碍。2）。长期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，引起NADPH氧化酶/黄嘌呤氧化酶活性的抑制，抑制氧化还原敏感性转录因子NF-κ B的活化，从而抑制MI诱导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轻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方法以及相关信号通路在MI后诱导的心力衰竭中的保护作用的研究。我们预计，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，除了目前用于治疗勃起功能障碍和肺动脉高压的临床用途。（流行病公共卫生相关性：急性心肌梗死（AMI）仍然是全球发病率和死亡率的主要原因。急性心肌梗死是由冠状动脉分支中的流动突然阻塞引起的，导致心肌缺血（缺氧）和组织死亡。AMI的长期并发症是晚期发生的左心室功能障碍（“心脏衰弱”）和心力衰竭。在这项提案中，我们将研究勃起功能障碍药物（伟哥，艾力达和西力士）和新的基因沉默方法的影响，以限制心肌梗死后心脏的损害。我们相信，从这些研究中获得的知识将为心脏病专家提供更多的工具，用于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选择来治疗患者的AMI和心室重塑。

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.