Abstract 9345: CaMKII Integrates Oxidative Stress and Calcium Signaling in Atrial Fibrillation
Introduction: Emerging evidence suggests that abnormal calcium (Ca2+) signaling and oxidative stress play an important role in Atrial Fibrillation (AF). We hypothesized that oxidative activation of CaMKII leads to increased sarcoplasmic reticulum (SR) Ca2+ release and delayed afterdepolarizations (DAD) to cause AF.
Methods: We established a mouse model of AF by implanting subcutaneous angiotensin II (Ang II) eluting osmotic pumps for three weeks followed by in vivo right atrial burst pacing. We measured oxidized CaMKII (ox-CaMKII) in atria from Ang II infused mice and from patients in AF or sinus rhythm. We developed ox-CaMKII resistant knock-in mice by replacing key methionines (281/282) with valines (MM-VV) in the predominant myocardial isoform (CaMKIIδ) and mice with transgenic myocardial expression of methionine sulfoxide reductase A (MsrA), an enzyme that reduces ox-CaMKII, to test if ox-CaMKII was required for AF promoted by Ang II.
Results: ox-CaMKII is elevated in atrial tissue from patients with AF and from mice infused with Ang II compared to patients in sinus rhythm or mice infused with saline. Mice treated with Ang II are highly susceptible to AF, while AF was rarely induced in saline infused mice. MM-VV mice and MsrA transgenic mice were resistant to AF and did not show increased ox-CaMKII after Ang II infusion. Atrial myocytes from Ang II treated wild type mice showed significantly increased DADs and SR Ca2+ sparks compared to saline treated controls. Ang II treatment did not increase calcium sparks in MM-VV mice.
Conclusions: Oxidative activation of CaMKII is an important molecular pathway for AF and strategies that decrease the level of ox-CaMKII can prevent AF.
- © 2012 by American Heart Association, Inc.