Oxidized CaMKII in Atrial Fibrillation

心房颤动中的氧化 CaMKII

• 批准号: 8628170
• 负责人: MARK E ANDERSON
• 金额: $ 37万
• 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: 2012-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628170
• 关键词: Am 80; Angiotensin II; Angiotensins; Animals; Antioxidants; Atrial Fibrillation; Automobile Driving; Cardiac; Cessation of life; Clinical Management; Complex; Elements; Event; Extracellular Matrix; Fibrosis; Figs - dietary; Gene Targeting; Healthcare Systems; Heart Atrium; Heart Diseases; Human; Individual; Infusion procedures; Knockout Mice; Maintenance; Maps; Matrix Metalloproteinases; Measures; Methionine; Modeling; Molecular; Molecular Target; Mus; Muscle Cells; Myocardial; NADPH Oxidase; Outcome; Pathologic Processes; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Predisposition; Process; Protein Isoforms; Public Health; Reactive Oxygen Species; Renin; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Transforming Growth Factors; Transgenic Organisms; Valine; antioxidant therapy; base; calmodulin-dependent protein kinase II; cost; design; improved; in vivo Model; innovation; meetings; methionine sulfoxide reductase; mouse model; novel; oxidation; prevent; research study; response; uptake

DESCRIPTION (provided by applicant): Our group identified a mechanism for CaMKII activation by oxidation of paired Met residues (281/282) in the CaMKII regulatory domain, and found that angiotensin II (Ang II) infusion leads to myocardial Met 281/282 oxidation, locking oxidized CaMKII (ox- CaMKII) into a persistently active configuration. We recently found that expression of ox- CaMKII is increased in atria from AF patients compared to controls, leading us to develop and validate a mouse model of Ang II infusion and enhanced AF susceptibility to test the potential role of ROS and ox-CaMKII in AF. We found that Ang II-infused mice with pacing-induced paroxysmal AF and mice with gene targeted myocardial expression of angiotensin converting enzyme and spontaneous AF, resembled AF patients by showing increased atrial ox-CaMKII. Our proposal will test the novel hypothesis that ox-CaMKII is a critical, but previously unrecognized, signaling mechanism for driving proarrhythmic events that favor AF using the following specific aims. 1. Determine if increased ox-CaMKII is necessary for proarrhythmic effects of Ang II on AF. Experiments planned in the aim will map the hypothesized 'upstream' elements of our proposed pathway and measure the contribution of NADPH oxidase, MsrA activity and CaMKII Met oxidation on ox-CaMKII levels and AF induction. 2. Determine if ox-CaMKII favors AF initiation. Studies in this aim will test a molecular and cellular mechanism 'downstream' to ox-CaMKII that we hypothesize explains increased AF induction by ox-CaMKII through increased SR Ca2+ uptake and release, inward INCX and delayed afterdepolarizations (DADs). 3. Determine if ox-CaMKII contributes to AF substrate through atrial enlargement and fibrosis. These experiments will determine if excessive ox-CaMKII contributes to proarrhythmic atrial remodeling by promoting expression of matrix metalloproteinase (favoring atrial enlargement), transforming growth factor b1 and atrial myocyte death (inducing reactive and reparative atrial fibrosis).

描述（由申请人提供）：我们的小组通过氧化 CaMKII 调节域中配对的 Met 残基 (281/282) 确定了 CaMKII 激活机制，并发现血管紧张素 II (Ang II) 输注导致心肌 Met 281/282 氧化，将氧化的 CaMKII (ox-CaMKII) 锁定为持久活性构型。我们最近发现，与对照组相比，AF 患者心房中 ox-CaMKII 的表达增加，因此我们开发并验证了 Ang II 输注和增强 AF 易感性的小鼠模型，以测试 ROS 和 ox-CaMKII 在 AF 中的潜在作用。我们发现，注射Ang II的起搏诱发阵发性房颤的小鼠和具有血管紧张素转换酶基因靶向心肌表达和自发性房颤的小鼠，与房颤患者相似，显示出心房ox-CaMKII增加。我们的提案将测试新的假设，即 ox-CaMKII 是一种关键但之前未被认识的信号机制，用于驱动有利于 AF 的致心律失常事件，具体目标如下。 1. 确定 ox-CaMKII 的增加是否是 Ang II 对 AF 的致心律失常作用所必需的。目标中计划的实验将绘制我们提出的途径的假设“上游”元素，并测量 NADPH 氧化酶、MsrA 活性和 CaMKII Met 氧化对 ox-CaMKII 水平和 AF 诱导的贡献。 2. 确定 ox-CaMKII 是否有利于 AF 启动。这一目标的研究将测试 ox-CaMKII“下游”的分子和细胞机制，我们假设该机制可以解释 ox-CaMKII 通过增加 SR Ca2+ 摄取和释放、向内 INCX 和延迟后除极 (DAD) 增加 AF 诱导。 3. 确定 ox-CaMKII 是否通过心房扩大和纤维化促进 AF 底物。这些实验将确定过量的ox-CaMKII是否通过促进基质金属蛋白酶的表达（有利于心房扩大）、转化生长因子b1和心房肌细胞死亡（诱导反应性和修复性心房纤维化）而导致心律失常性心房重构。