CaMKII regulates key mechanisms of vascular response to injury in vivo

CaMKII 调节体内血管损伤反应的关键机制

• 批准号: 8459392
• 负责人: Isabella Maria Grumbach
• 金额: $ 35.94万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459392
• 关键词: Atherosclerosis; Balloon Angioplasty; Binding; Blood Vessels; Calmodulin; Cardiovascular system; Cause of Death; Coronary Artery Bypass; Data; Dependence; Development; Disease; Disease Resistance; Endarterectomy; Endothelium; Enzymes; Equilibrium; Event; Fostering; Goals; Growth Factor; Health; Health Care Costs; Hyperplasia; In Vitro; Injury; Knowledge; Lead; Ligation; Mediating; Medicine; Mission; Morbidity - disease rate; Muscle Contraction; Myocardial Infarction; Operative Surgical Procedures; Outcome; Pathway interactions; Phosphotransferases; Prevention strategy; Protein-Serine-Threonine Kinases; Public Health; Publishing; Regulation; Research; Role; Signal Transduction; Site; Stents; Stroke; Testing; Therapeutic; Translating; Validation; Vascular Smooth Muscle; Veins; Work; base; calmodulin-dependent protein kinase II; cytokine; design; graft failure; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; meetings; methionine sulfoxide reductase; migration; neointima formation; novel; novel strategies; oxidation; prevent; programs; response; response to injury; restenosis; tool

DESCRIPTION (provided by applicant): The function of the multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) remains poorly understood in the vasculature. Our data suggest that CaMKII is instrumental in mediating neointima formation and remodeling after vascular injury. Neointima formation and remodeling occur in vein graft failure after coronary artery bypass surgery, after balloon angioplasty and surgical endarterectomy and have a significant impact in terms of morbidity and health care cost. Our long-term goal is to study the function of CaMKII in the vasculature, specifically CaMKII modulation as new approach to treat vascular injury. The objective of this application is to determine how CaMKII is activated in injury, directy test whether CaMKII inhibition will confer disease resistance in vascular injury and delineate the dependance of VSMC migration and proliferation upon the oxidative activation of CaMKII. The central hypothesis of this application is that CaMKII is activated by oxidation of Met281/282 in vascular injury and that oxidative activation of CaMKII is necessary for neointimal hyperplasia, VSMC proliferation and migration. This hypothesis is based on our preliminary data that CaMKII is essential in neointima formation and remodeling after injury. Oxidized CaMKII (ox-CaMKII) is readily detected in the neointima after vascular injury. In addition, we have compelling evidence that key activators in the response to injury induce ox-CaMKII in vitro. The rationale of the proposed research is that understanding how CaMKII is activated after vascular injury, has the potential to translate into better strategies to prevent the deleterious effects after vascular injry. Guided by strong preliminary data, the central hypothesis will be tested in three specific aims: 1) Dissect the mechanisms of CaMKII activation in vascular injury in vivo; 2) Determine the role of methionine sulfoxide reductase A (MsrA), the enzyme that controls the balance between active ox-CaMKII and reduced inactive CaMKII, in the response to injury; 3) Dissect the mechanisms of CaMKII activation in VSMC migration, proliferation in vitro. In the first aim, a novel in vivo model will be used to test if the blockade of oxidative CaMKII activation is sufficient to abrogate the response to injury. Under aim 2, we will define whether MsrA can modulate neointimal hyperplasia through ox-CaMKII. In aim 3, we will delineate how CaMKII is activated by key cytokines and growth factors relevant for vascular injury in vitro and how the activation pathways correlate with VSMC migration and proliferation. The approach is innovative because of its use of novel in vivo models and specific tools to dissect CaMKII signaling. The proposed research is significant because it is expected to advance the field by identifying CaMKII activating events in vivo. Ultimately, such knowledge may allow for the development of new preventive strategies for vascular injury.

描述（由申请人提供）：多功能 Ca2+/钙调蛋白依赖性激酶 II (CaMKII) 在脉管系统中的功能仍然知之甚少。我们的数据表明 CaMKII 有助于介导血管损伤后的新内膜形成和重塑。新内膜形成和重塑发生在冠状动脉搭桥手术、球囊血管成形术和动脉内膜切除术后的静脉移植失败中，并对发病率和医疗费用产生重大影响。我们的长期目标是研究 CaMKII 在脉管系统中的功能，特别是 CaMKII 调节作为治疗血管损伤的新方法。本申请的目的是确定CaMKII在损伤中如何被激活，直接测试CaMKII抑制是否会赋予血管损伤抗病性，并描绘VSMC迁移和增殖对CaMKII氧化激活的依赖性。本申请的中心假设是CaMKII在血管损伤中通过Met281/282的氧化而被激活，并且CaMKII的氧化激活对于新内膜增生、VSMC增殖和迁移是必需的。这一假设基于我们的初步数据，即 CaMKII 对于损伤后的新内膜形成和重塑至关重要。血管损伤后的新内膜中很容易检测到氧化 CaMKII (ox-CaMKII)。此外，我们有令人信服的证据表明损伤反应中的关键激活剂在体外诱导 ox-CaMKII。这项研究的基本原理是，了解 CaMKII 在血管损伤后如何被激活，有可能转化为更好的策略来预防血管损伤后的有害影响。在强有力的初步数据的指导下，中心假设将在三个具体目标上得到检验：1) 剖析CaMKII激活在体内血管损伤中的机制； 2) 确定蛋氨酸亚砜还原酶 A (MsrA) 在损伤反应中的作用，该酶控制活性 ox-CaMKII 和还原性非活性 CaMKII 之间的平衡； 3) 解析CaMKII激活在VSMC迁移、体外增殖中的机制。第一个目标是使用一种新型体内模型来测试氧化 CaMKII 激活的阻断是否足以消除 对伤害的反应。在目标 2 下，我们将定义 MsrA 是否可以通过 ox-CaMKII 调节新生内膜增生。在目标 3 中，我们将描述 CaMKII 如何被体外血管损伤相关的关键细胞因子和生长因子激活，以及激活途径如何与 VSMC 迁移和增殖相关。该方法具有创新性，因为它使用新颖的体内模型和特定工具来剖析 CaMKII 信号传导。这项研究意义重大，因为它有望通过识别体内 CaMKII 激活事件来推进该领域的发展。最终，这些知识可能有助于开发新的血管损伤预防策略。