Methionine sulfoxide reductase A and oxidized CaMKII in structural heart disease

项目摘要/摘要 这一竞争性续订申请旨在测试关于以下角色的三个新假设 过度氧化应激与钙调蛋白激酶II(CaMKII)在心肌损伤中的作用 心肌梗塞(MI)和醛固酮(ALDO)。这些研究将使用由 线粒体CaMKII、氧化型CaMKII(OX-CaMKII)和蛋氨酸亚砜的活性 还原酶A(MSRA)是一种还原和失活OX-CaMKII的酶，受到控制。每一位 相互关联但独立的AIMS得到了强劲的初步数据的支持。 目的1探讨Aldo和OX-CaMKII在心肌梗死后心脏破裂中的作用。我们将确定奥尔多是否 通过增强NADPH氧化酶和OX-CaMKII增加心肌梗死后破裂的频率，并解开一个 此前未知的OX-CaMKII驱动心肌基质金属蛋白酶9(MMP9)的途径 通过HDAC4/5磷酸化和MEF2去阻遏表达。 目的2探讨OX-CaMKII在心肌肥厚中的作用。CaMKII对心肌的贡献 心肌肥厚，但OX-CaMKII途径在心肌肥厚中的潜在作用尚不清楚。我们 将测试心肌OX-CaMKII一致促进基质转录的新概念 重塑(在目标1)和肥大基因程序(在目标2)通过HDAC4/5磷酸化和 MEF2去阻抑作用。 目的3确定OX-CaMKII在肥厚向心力衰竭转变过程中的作用。我们的预赛 研究表明，CaMKII存在于线粒体中，而线粒体OX-CaMKII在线粒体中起着重要的作用 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 预测线粒体靶向CaMKII抑制将显著延迟和线粒体靶向 CaMKII的过度表达将显著加速心力衰竭的发展。

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.