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:
  • 金额:
    $ 37万
  • 依托单位:
  • 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

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 急性心肌梗死(AMI)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AMI。急性心肌梗死是由突发的 导致心肌梗塞的冠状动脉分支中的流动的血栓性阻塞 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的左室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,包括枸橼酸西地那非(伟哥), 和伐地那非(Levitra)诱导强大的心脏保护作用,对抗缺血- 再灌注损伤(I/R)在各种动物和细胞模型。这样做的目的 应用是为了进一步证明这些药物对 心肌梗死(MI)引起的心力衰竭,并开发创新的方法, 持久的保护。我们将测试以下假设:1)PDE的抑制- 5A与新型抑制剂或靶向基因沉默与慢病毒载体, 体内减少MI后诱导的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 抑制通过增加生物利用度抑制氧化/亚硝化应激 NO,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的激活,从而抑制 心肌梗死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(PKG)的体内基因转移减弱了后 心肌梗塞引起的重塑和心力衰竭。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 心肌梗塞后诱发心力衰竭的方法和相关信号通路。我们 预计这些调查的结果将为扩大 PDE-5A抑制剂除了用于治疗心血管疾病外, 目前临床上用于治疗勃起功能障碍和肺动脉高压。通俗叙事 急性心肌梗死(AMI)仍然是发病的主要原因, 全世界的死亡率。急性心肌梗死是由冠状动脉血流突然受阻引起的, 动脉分支导致心肌缺血(缺氧)和组织死亡。的 AMI的远期并发症是迟发性左室功能不全 (“心脏衰弱”)和心力衰竭。在这项建议中,我们会研究 勃起功能障碍药物(伟哥,艾力达和西力士)和新的基因沉默 限制AMI后心脏损害的方法。我们相信知识 从这些研究中得出的结论将为心脏病专家提供额外的治疗工具 治疗心脏衰竭的药物另外我们 研究将为治疗AMI开辟另一种创新的基因沉默选择, 患者的心室重构。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Rakesh C Kukreja其他文献

Sildenafil Citrate (Viagra) Induces Cardioprotective Effects after Ischemia/Reperfusion Injury in Infant Rabbits
柠檬酸西地那非(伟哥)可诱导幼兔缺血/再灌注损伤后的心脏保护作用
  • DOI:
    10.1203/01.pdr.0000147736.27672.15
  • 发表时间:
    2005-01-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Yvonne A Bremer;Fadi Salloum;Ramzi Ockaili;Eric Chou;William B Moskowitz;Rakesh C Kukreja
  • 通讯作者:
    Rakesh C Kukreja

Rakesh C Kukreja的其他文献

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{{ truncateString('Rakesh C Kukreja', 18)}}的其他基金

BMP-7 Modulates Inflammation induced cell death in Diabetic Cardiac and Skeletal Muscle
BMP-7 调节糖尿病心肌和骨骼肌炎症诱导的细胞死亡
  • 批准号:
    9788441
  • 财政年份:
    2018
  • 资助金额:
    $ 37万
  • 项目类别:
BMP-7 Modulates Inflammation induced cell death in Diabetic Cardiac and Skeletal Muscle
BMP-7 调节糖尿病心肌和骨骼肌炎症诱导的细胞死亡
  • 批准号:
    10242150
  • 财政年份:
    2018
  • 资助金额:
    $ 37万
  • 项目类别:
Amelioration of Doxorubicin Induced Muscle Dysfunction with Embryoinic stem cells-Derived Exosomes
利用胚胎干细胞来源的外泌体改善阿霉素引起的肌肉功能障碍
  • 批准号:
    10322656
  • 财政年份:
    2018
  • 资助金额:
    $ 37万
  • 项目类别:
BMP-7 Modulates Inflammation induced cell death in Diabetic Cardiac and Skeletal Muscle
BMP-7 调节糖尿病心肌和骨骼肌炎症诱导的细胞死亡
  • 批准号:
    10376557
  • 财政年份:
    2018
  • 资助金额:
    $ 37万
  • 项目类别:
ROS, Inflammation, and Cardioprotection in Type 2 Diabetes
2 型糖尿病中的 ROS、炎症和心脏保护
  • 批准号:
    8701394
  • 财政年份:
    2013
  • 资助金额:
    $ 37万
  • 项目类别:
ROS, Inflammation, and Cardioprotection in Type 2 Diabetes
2 型糖尿病中的 ROS、炎症和心脏保护
  • 批准号:
    8522552
  • 财政年份:
    2013
  • 资助金额:
    $ 37万
  • 项目类别:
Health Educational Research Opportunities (HERO)
健康教育研究机会(HERO)
  • 批准号:
    7797605
  • 财政年份:
    2008
  • 资助金额:
    $ 37万
  • 项目类别:
Health Educational Research Opportunities (HERO)
健康教育研究机会(HERO)
  • 批准号:
    7617652
  • 财政年份:
    2008
  • 资助金额:
    $ 37万
  • 项目类别:
Cardioprotective Signaling following Phosphodiesterase-5 Inhibition
磷酸二酯酶 5 抑制后的心脏保护信号传导
  • 批准号:
    7867829
  • 财政年份:
    2008
  • 资助金额:
    $ 37万
  • 项目类别:
Health Educational Research Opportunities (HERO)
健康教育研究机会(HERO)
  • 批准号:
    8056464
  • 财政年份:
    2008
  • 资助金额:
    $ 37万
  • 项目类别:

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