Abstract 14037: Angiotensin II Promotes Atrial Fibrillation in Mice by CaMKII Oxidation
Introduction: Atrial Fibrillation (AF) is favored by Angiotensin II (Ang II) and reactive oxygen species (ROS), but the mechanism is unknown. We hypothesized that Ang II causes oxidative activation of calcium-calmodulin kinase II (CaMKII), leading to increased SR calcium (Ca2+) release by ryanodine receptor (RyR2) phosphorylation and thus promoting AF.
Methods: We established a mouse model of AF by implanting subcutaneous Ang II eluting osmotic pumps (2000 ng/kg/min) for three weeks. After three weeks, in vivo burst pacing was performed in the right atrium of anesthetized mice to induce AF. We used antibodies against oxidized and total CaMKII, for immunofluorescence imaging and immunoblotting of mouse hearts or human right atrial tissue from patients with and without AF.
Results: Atrial tissue from patients with AF and Ang II treated mice showed higher oxidized CaMKII signal as compared to controls. Ang II treated wild type mice showed a high degree of inducible AF as compared to saline treated mice. Ang II treated mice also demonstrate a high frequency of spontaneous Ca2+ sparks and delayed afterdepolarizations. We developed knock-in mice with MM281/282VV mutation in CaMKII (oxidation resistant) and these mice (VV) are resistant to AF. p47-/- mice lacking functional NADPH oxidase and therefore less Ang II mediated ROS are also resistant to AF. Similarly, AC3-I mice (expressing CaMKII inhibitory peptide), and knock-in mice with S2814A RyR2 (resistant to CaMKII dependent phosphorylation) did not develop AF after treatment with Ang-II.
Conclusions: Oxidized CaMKII is increased in atrial tissue from patients with AF and in our Ang II infusion mouse model of AF. Elevated Ang II increases oxidized CaMKII and promotes AF. Strategies that prevent oxidation of CaMKII or inhibit CaMKII activity prevent Ang-II mediated AF in mice.
- © 2011 by American Heart Association, Inc.