Oxidized CaMKII in Atrial Fibrillation

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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).