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）：我们的小组通过对CAMKII调节域中配对的MET残基（281/282）进行氧化来确定CAMKII激活的机制，并发现血管紧张素II（ANG II）输注会导致心肌MET 281/282 MET 281/282氧化，锁定氧化Camkkii（Ox-camkkii（ox-camkii）camkii（ox-camkii）。我们最近发现，与对照组相比，心房患者的心房中牛CamkII的表达增加，这使我们开发和验证了ANG II输注的小鼠模型，并增强了AF易感性，以测试ROS和OX-CAMKII在AF中的潜在作用。我们发现，具有起搏诱导的阵发性AF和具有基因的靶向心肌表达的血管紧张素转化酶和自发性AF的基因表达的ANG II注入的小鼠与AF患者相似，通过表现出增加的心房牛Camkii，与AF患者相似。我们的建议将检验一个新的假设，即OX-CAMKII是一种关键但未识别的信号传导机制，用于驱动使用以下特定目的的促进AF的动脉心律失常事件。 1。确定增加的OX-CAMKII是否对于ANG II对AF的心律失常作用是必需的。目标中计划的实验将绘制我们提出的途径的假设的“上游”元素，并衡量NADPH氧化酶，MSRA活性和CAMKII对OX-CAMKII水平和AF诱导的氧化的贡献。 2。确定ox-camkii是否有利于AF启动。在此目标中的研究将测试一种分子和细胞机制“下游”到OX-CAMKII，我们假设通过增加的SR Ca2+摄取和释放，内向INCX并延迟了过度极化（DADS），我们假设Ox-CamkII的AF诱导增加了AF诱导。 3。确定OX-CAMKII是否通过心房增大和纤维化有助于AF底物。这些实验将通过促进基质金属蛋白酶的表达（有利于心房增大），转化生长因子B1和心房心肌死亡（诱导反应性和再生性纤维化）来确定过量的OX-CAMKII是否促进了心律失常的心房重塑。