Calcium/Calmodulin Activated Kinases in Smooth Muscle

血管平滑肌(VSM)细胞的迁移和增殖发生在发育、创伤 愈合，血管生成，并有助于血管疾病的进展。已知的是Ca2+信号 调节细胞增殖和运动，尽管这一知识还没有很好地整合到分子中 模型，部分原因是缺乏对钙依赖的效应机制和靶点的洞察。正在进行的工作 由这笔赠款资助的研究重点是一个主要的钙信号效应器的结构和功能，即 多功能钙/钙调蛋白依赖性蛋白激酶II(CaMKII)。 VSM细胞的迁移和增殖是尚未获得或 有丢失的、分化的收缩蛋白标记物和功能。VSM的表型调控在 分化的收缩和增殖/迁移状态具有相当大的兴趣和临床重要性， 但并不完全被理解。一个与上一个供资期间的结果相一致的新概念是 疾病或损伤导致的钙信号机制和动力学的变化有助于 促进血管壁重塑的迁移/增殖性VSM表型的发展。整体而言 这次更新的目的是测试钙离子通过特定的CaMKII亚型信号转导调节VSM的概念 基因转录，是VSM表型的决定因素。 这一概念将通过追求三个目标来检验：1.我们将检验CaMKII调节 合成表型VSM中的共抑制因子HDAC4和HDAC5。转录激活子MEF2将是 被测试为CaMKII/HDAC4，5依赖的靶标，影响基因转录。CaMKII亚型特异性 与这一调控途径的偶联作用进行测试。2.)CaMKII同工酶作为细胞周期调控因子的功能 将评估转录抑制因子REST/NRSF在VSM中的表达和活性，并将HDAC4/5 作为中间人进行了测试。3.)CaMKII对HDAC4/5和REST的调节作用 VSM表型和血管重塑将使用球囊损伤的大鼠颈动脉在体内进行评估 作为一名模特。 通过阐明CaMKII亚型调节对血管损伤的反应的功能后果， 这些研究的结果有望为表型的潜在机制提供见解。 血管平滑肌细胞的调制及钙信号传导机制(S) 多功能蛋白激酶调节VSM细胞功能，参与血管疾病的发生。

Migration and proliferation of vascular smooth muscle (VSM) cells occurs during development, wound healing, angiogenesis, and contributes to the progression of vascular disease. Ca2+ signals are known to regulate cell proliferation and motility, although this knowledge has not been well integrated into molecular models, due in part to lack of insight into Ca2+-dependent effector mechanisms and targets. Ongoing work funded by this grant has focused on the structure and function of one major Ca2+ signal effector, namely multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII). VSM cell migration and proliferation are properties of "synthetic phenotype" cells that have not acquired, or have lost, differentiated contractile protein markers and function. VSM phenotype modulation between differentiated contractile and proliferative/migratory states are of considerable interest and clinical importance, but are incompletely understood. An emerging concept, consistent with results from the past funding period, is that disease- or injury-induced changes in Ca2+ signaling mechanisms and dynamics contributes to development of the migratory/proliferative VSM phenotype promoting vascular wall remodeling. The overall objective of this renewal is to test the concept that Ca2+ signaling via specific CaMKII isoforms, regulates VSM gene transcription and is a determinant of VSM phenotype. This concept will be tested by pursuing three aims: 1.) We will test the hypothesis that CaMKII regulates the co-repressors HDAC4 and HDAC5 in synthetic phenotype VSM. The transcription activator MEF2 will be tested as a CaMKII/HDAC4,5-dependent target affecting gene transcription. CaMKII isoform specificity in coupling to this regulatory pathway be tested. 2.) The function of CaMKII isozymes as regulators of the transcriptional repressor REST/NRSF expression and activity in VSM will be evaluated and HDAC4/5 will be tested as intermediaries. 3.) The function of CaMKII-dependent regulation of HDAC4/5 and REST in regulating VSM phenotype and vascular remodeling will be evaluated in vivo using the balloon-injured rat carotid artery as a model. By elucidating the functional consequences of CaMKII isoform modulation in response to vascular injury, the results of these studies are expected to provide insights into mechanisms underlying phenotypic modulation of VSM cells and mechanism(s) by which Ca2+ signals and a prominent Ca2+-dependent multifunctional protein kinase modulates VSM cell function and contributes to vascular disease.