Methionine sulfoxide reductase A and oxidized CaMKII in structural heart disease

蛋氨酸亚砜还原酶 A 和氧化 CaMKII 在结构性心脏病中的作用

• 批准号: 8386984
• 负责人: MARK E ANDERSON
• 金额: $ 35.94万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-23 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386984
• 关键词: Adrenergic Receptor; Agonist; Aldosterone; Angiotensin II; Back; Binding; Ca(2+)-Calmodulin Dependent Protein Kinase; Calmodulin; Cause of Death; Cell Death; Cell Membrane Permeability; Cessation of life; Cytoplasm; Data; Development; Enzymes; Equilibrium; Event; Figs - dietary; Frequencies; Functional disorder; Funding; Gelatinase B; Genes; Genetic; Genetic Transcription; Goals; HDAC4 gene; Heart; Heart Diseases; Heart failure; Hospitalization; Hyperactive behavior; Hypertrophy; Isoproterenol; Malignant Neoplasms; Mitochondria; Molecular Conformation; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial rupture; Myocardium; NADPH Oxidase; Natural History; Outcome; Oxidative Stress; Pathway interactions; Patients; Phosphorylation; Play; Predisposition; Public Health; Reactive Oxygen Species; Research; Risk; Role; Rupture; Signal Transduction; Sudden Death; Testing; Therapeutic; United States; Ventricular Remodeling; Work; abstracting; base; calmodulin-dependent protein kinase II; derepression; design; effective therapy; improved; innovation; meetings; methionine sulfoxide reductase; mortality; mouse model; novel; oxidation; programs; response

Project Summary/Abstract This competitive renewal application is designed to test three new hypotheses about the role of excessive oxidative stress and calmodulin kinase II (CaMKII) in pathological responses to myocardial infarction (MI) and aldosterone (Aldo). These studies will use new genetic mouse models developed by us where the activity of mitochondrial CaMKII, oxidized CaMKII (ox-CaMKII) and methionine sulfoxide reductase A (MsrA), the enzyme that reduces and inactivates ox-CaMKII, are controlled. Each of the inter-related, but independent aims is backed by strong preliminary data. Aim 1 Determine how Aldo and ox-CaMKII promote cardiac rupture after MI. We will determine if Aldo increases the frequency of post-MI rupture by enhancing NADPH oxidase and ox-CaMKII, and unravel a previously unknown pathway where ox-CaMKII drives myocardial matrix metalloproteinase 9 (MMP9) expression by HDAC4/5 phosphorylation and MEF2 derepression. Aim 2 Determine the role of ox-CaMKII in myocardial hypertrophy. CaMKII contributes to myocardial hypertrophy, but the potential role of the ox-CaMKII pathway in myocardial hypertrophy is unknown. We will test the novel concept that myocardial ox-CaMKII coherently promotes transcription of matrix remodeling (in Aim 1) and hypertrophic gene programs (in Aim 2) by HDAC4/5 phosphorylation and MEF2 derepression. Aim 3 Determine the role of ox-CaMKII in the transition from hypertrophy to heart failure. Our preliminary studies indicate that CaMKII is resident in mitochondria and that mitochondrial ox-CaMKII plays a decisive role in mitochondria membrane permeability transition pore (mPTP) opening and cell death. We predict that mitochondrial-targeted CaMKII inhibition will significantly delay and mitochondrial-targeted CaMKII over-expression will significantly hasten development of heart failure.

项目总结/摘要 此竞争性续约申请旨在测试三个新的假设， 过度氧化应激和钙调蛋白激酶II（CaMKII）在心肌缺血病理反应中的作用 梗死（MI）和醛固酮（Aldo）。这些研究将使用新的遗传小鼠模型， 其中线粒体CaMKII、氧化CaMKII（ox-CaMKII）和甲硫氨酸亚砜的活性 还原酶A（MsrA），还原和灭活ox-CaMKII的酶，受到控制。每个 相互关联但独立的目标得到了强有力的初步数据的支持。 目的1确定Aldo和ox-CaMKII如何促进MI后心脏破裂。我们会确定奥尔多 通过增强NADPH氧化酶和ox-CaMKII增加心肌梗死后破裂的频率，并解开心肌梗死后破裂的机制。 ox-CaMKII驱动心肌基质金属蛋白酶9（MMP 9）的先前未知途径 通过HDAC 4/5磷酸化和MEF 2去阻遏表达。 目的2探讨ox-CaMK Ⅱ在心肌肥厚中的作用。CaMKII有助于心肌细胞 心肌肥大，但ox-CaMKII途径在心肌肥大中的潜在作用尚不清楚。我们 将测试心肌ox-CaMKII相干促进基质转录的新概念， 通过HDAC 4/5磷酸化的重塑（在目标1中）和肥大基因程序（在目标2中）， MEF 2去阻遏。 目的3确定ox-CaMKII在心肌肥厚向心力衰竭转变中的作用。我们的初步 研究表明CaMKII存在于线粒体中，线粒体ox-CaMKII在线粒体中起着重要作用。 在线粒体膜通透性转换孔（mPTP）开放和细胞死亡中起决定性作用。我们 预测靶向于尿道的CaMKII抑制将显著延迟和靶向于尿道的 CaMKII过度表达将显著加速心力衰竭的发展。