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: 9029343
• 负责人: Isabella Maria Grumbach
• 金额: $ 37.75万
• 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 2017-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029343
• 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; 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; Vein graft; 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(申请人提供)：多功能钙/钙调蛋白依赖的激酶II(CaMKII)的功能在血管系统中仍然知之甚少。我们的数据表明，CaMKII在调节血管损伤后新生内膜的形成和重塑中起着重要作用。冠状动脉搭桥术、球囊血管成形术和外科动脉内膜剥脱术后移植静脉失败时会发生新生内膜的形成和重塑，对发病率和医疗费用有重大影响。我们的长期目标是研究CaMKII在血管系统中的功能，特别是CaMKII的调节作为治疗血管损伤的新途径。本应用的目的是确定CaMKII在损伤中是如何被激活的，直接测试抑制CaMKII是否在血管损伤中具有抗病能力，并描绘VSMC迁移和增殖对CaMKII氧化激活的依赖。这一应用的中心假设是，在血管损伤中，CaMKII是由Met281/282的氧化激活而激活的，而CaMKII的氧化激活是新生内膜增生、VSMC增殖和迁移所必需的。这一假说是基于我们的初步数据，即CaMKII在损伤后新生内膜的形成和重塑中是必不可少的。氧化型CaMKII(OX-CaMKII)很容易在血管损伤后的新生内膜中检测到。此外，我们有令人信服的证据表明，损伤反应中的关键激活物在体外诱导OX-CaMKII。这项拟议的研究的基本原理是，了解血管损伤后CaMKII是如何被激活的，有可能转化为更好的策略来预防血管损伤后的有害影响。在强劲的初步数据的指导下，中心假设将在三个具体目标上进行检验：1) 分析CaMKII激活在体内血管损伤中的作用机制；2)确定控制激活的ox-CaMKII和还原的失活CaMKII之间的平衡的蛋氨酸亚砜还原酶A(MSRA)在损伤反应中的作用；3)剖析CaMKII激活在体外VSMC迁移、增殖中的作用机制。在第一个目标中，将使用一个新的体内模型来测试对氧化CaMKII激活的阻断是否足以消除 对受伤的反应。在目标2中，我们将确定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是如何在体外被与血管损伤相关的关键细胞因子和生长因子激活的，以及激活途径如何与VSMC迁移和增殖相关。这种方法是创新的，因为它使用了新的活体模型和特定的工具来剖析CaMKII信号。这项拟议的研究意义重大，因为它有望通过识别体内CaMKII激活事件来推动这一领域的发展。最终，这些知识可能有助于开发新的血管损伤预防策略。