PKC Epsilon in Vascular Dysfunction

PKC Epsilon 在血管功能障碍中的应用

• 批准号: 8329950
• 负责人: Wei Zhou
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329950
• 关键词: Acute; Animal Model; Atherosclerosis; Binding; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Plaques; Cause of Death; Cell model; Cells; Cellular Stress; Clinical; Clinical Research; Coculture Techniques; Complication; Critical Pathways; Developed Countries; Diabetes Mellitus; Disease; Disease Progression; Distress; Etiology; Foundations; Functional disorder; Goals; Heart Atrium; Human; Hyperplasia; Injury; Insulin; Insulin Resistance; Intervention; Investigation; Ischemia; Knowledge; Laboratories; Matrix Metalloproteinases; Mediating; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Models; Mus; Myocardium; Outcome; Patients; Peptides; Population; Procedures; Process; Production; Proteomics; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Research; Risk; Role; Signal Pathway; Smooth Muscle Myocytes; Solid; System; Therapeutic; Time; Tissues; Transgenic Organisms; Translating; Transplantation; aldehyde dehydrogenases; base; cardiovascular risk factor; cell injury; clinically relevant; diabetic; improved; in vivo; innovation; macrophage; molecular modeling; new therapeutic target; novel; novel therapeutics; protein kinase C epsilon; resistin; restenosis; treatment strategy

DESCRIPTION (provided by applicant): Atherosclerosis is the leading cause of death in the developed countries. Diabetes mellitus markedly increases the risk of atherosclerotic complications. Emerging evidence suggests that resistin, a novel adipokine implicated in insulin resistin, contributes to atherosclerotic disease and the poor interventional outcomes among diabetic population. We and others have shown that resistin significantly induces vascular smooth muscle cell (VSMC) dysfunction, a key step in intimal hyperplasia and restenosis. However, little is known about the underlying mechanisms and the treatment option is largely lacking. Recently, we demonstrated that the cellular effect of resistin was mediated by PKC-[. Our research team also showed that activating PKC-¿ protected against ischemia/reperfusion injury of transplanted myocardium and inhibiting PKC-¿ mitigated intimal hyperplasia in rat. Although therapeutically targeting PKC-¿ in the treatment of atherosclerotic complications is largely unknown. Based on our novel, seemingly controversial observations, we believe that the involvement of PKC-¿ in cardiovascular disease is a dynamic process. Acute activation of PKC-¿ protects against ischemia/reperfusion-induced cellular injuries whereas sustained inhibition of PKC-¿ following procedures can minimize resistin-induced intimal hyperplasia and restenosis. It is our fundamental hypothesis that time-specific PKC-¿ modulation reduces resistin-induced intimal hyperplasia and restenosis. To pursue this hypothesis, we propose a more comprehensive investigation to elucidate the molecular mechanisms, cellular effects, and in vivo influences of PKC-¿ modulation in resistin-exaggerated cellular stress following vascular injury. Three specific aims (SA) are proposed. SA 1: Determine the role of PKC-¿ in resistin-induced cellular effects. In this SA, we will first confirm our preliminary findings and determine time-specific PKC-¿ modulation in VSMC. We will then explore the modulating effect of PKC-¿ using a novel activated macrophage-VSMC co-culture system. Lastly, we will verify the effects of resistin and PKC-¿ modulation in ex vivo human carotid plaques. SA 2: Characterize the molecular mechanisms of PKC-¿-dependent resistin-induced cellular distress. Using a HCASMC model, we will study the involvement of PKC-¿ in resistin-induced ROS over-production in the SA2a. We will also expand our preliminary observation by examining time-specific PKC-¿ modulation in known resistin-induced signaling pathways in SA2b. Lastly, we will explore novel PKC-¿-dependent downstream signaling pathway(s) using an unbiased proteomics approach and determine whether a novel PKC-¿-mediated molecular interaction, mitochondria aldehyde dehydrogenase (ALDH2), is involved in resistin- induced cellular dysfunction (SA2c). SA 3: Evaluate the effects PKC-¿ on resistin-augmented post-injury intimal hyperplasia in a murine model. We will independently modulate PKC-¿ before atrial clamping and after vascular interventions to determine the in vivo effects of time-specific PKC-¿ modulation on resistin-exacerbated intimal hyperplasia using a transgenic murine model. The potential application of novel PKC-¿ specific peptide modulators at specific time points, justified by successful completion of our aims, represents a novel therapeutic option. Deciphering clinically-relevant mechanism(s) of intimal hyperplasia and ultimately translating these into a novel therapeutic strategy to suppress disease progression supports our long-term goal of minimizing complications of cardiovascular diseases and improving the clinical outcome of cardiovascular procedures.

描述（由申请人提供）： 动脉粥样硬化是发达国家死亡的主要原因。糖尿病明显增加了动脉粥样硬化并发症的风险。新兴的证据表明，抗蛋白是一种涉及胰岛素抵抗素的新型脂肪因子，在糖尿病人群中有助于动脉粥样硬化疾病和介入不良的介入结局。我们和其他人表明，抵抗素显着影响血管平滑肌细胞（VSMC）功能障碍，这是内膜增生和再狭窄的关键步骤。但是，对于基本机制和治疗方案几乎没有什么了解。最近，我们证明了抗蛋白的细胞作用是由PKC- [。我们的研究团队还表明，激活PKC- - 免受移植心肌的缺血/再灌注损伤，并抑制大鼠中的PKC-缓解内膜增生。基于我们的新颖，看似有争议的观察，我们认为PKC- - 在心血管疾病中的参与是一个动态过程。 PKC- - 急性激活可预防缺血/再灌注诱导的细胞损伤，而持续抑制PKC-？遵循程序可以最大程度地减少抵抗素诱导的内膜增生和再狭窄。我们的基本假设是，时间特异性的PKC-调节减少了抵抗素诱导的内膜增生和再狭窄。为了提出这一假设，我们提出了一项更全面的研究，以阐明PKC- - 在血管损伤后抵抗素夸大的细胞应激调节的分子机制，细胞效应和体内影响。提出了三个具体目标（SA）。 SA 1：确定PKC- - 在抵抗蛋白诱导的细胞作用中的作用。在此SA中，我们将首先确认我们的初步发现，并确定VSMC中特定时间的PKC-调制。然后，我们将使用一种新型的激活巨噬细胞-VSMC共培养系统探索PKC- - 的调制效果。最后，我们将验证在体内人类颈动脉斑块中抵抗素和PKC-调节的影响。 SA 2：表征了依赖PKC-依赖性抵抗蛋白诱导的细胞困扰的分子机制。使用HCASMC模型，我们将研究PKC- - SA2A中PKC- - 抗蛋白诱导的ROS过量产生的参与。我们还将通过检查SA2B中已知抵抗蛋白诱导的信号通路中的时间特异性PKC-调制来扩展初步观察。最后，我们将使用无偏的蛋白质组学方法探索新颖的PKC-e依赖性下游信号通路（S），并确定新型的PKC-®介导的分子相互作用，线粒体醛醛脱氢酶（ALDH2）是否参与了抵抗蛋白诱导的细胞诱导的细胞诱导的细胞诱导的脱氢酶（ALDH2）。 SA 3：评估鼠模型中对抗素激增后伤害后损伤增生的影响。我们将在心房夹紧之前和血管干预后独立调节PKC- - 确定使用转基因鼠模型对时间特异性PKC-¿调制对抗素染色蛋白异内增生的体内影响。通过成功完成我们的目标是合理的特定时间点，新型PKC-特定肽调节剂的潜在应用代表了一种新型的治疗选择。破解内膜增生的临床临床机制，并最终将其转化为一种新型的治疗策略，以抑制疾病进展，这支持了我们的长期目标，即最大程度地减少心血管疾病并发症并改善心血管手术的临床结果。