Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure
Shin Yoo, Gary Aistrup, Yohannes Shiferaw, Jason Ng, Peter J. Mohler, Thomas J. Hund, Trent Waugh, Suzanne Browne, Georg Gussak, Mehul Gilani, Bradley P. Knight, Rod Passman, Jeffrey J. Goldberger, J. Andrew Wasserstrom, Rishi Arora
Shin Yoo, Gary Aistrup, Yohannes Shiferaw, Jason Ng, Peter J. Mohler, Thomas J. Hund, Trent Waugh, Suzanne Browne, Georg Gussak, Mehul Gilani, Bradley P. Knight, Rod Passman, Jeffrey J. Goldberger, J. Andrew Wasserstrom, Rishi Arora
View: Text | PDF
Research Article Cardiology

Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure

Abstract

The precise mechanisms by which oxidative stress (OS) causes atrial fibrillation (AF) are not known. Since AF frequently originates in the posterior left atrium (PLA), we hypothesized that OS, via calmodulin-dependent protein kinase II (CaMKII) signaling, creates a fertile substrate in the PLA for triggered activity and reentry. In a canine heart failure (HF) model, OS generation and oxidized-CaMKII–induced (Ox-CaMKII–induced) RyR2 and Nav1.5 signaling were increased preferentially in the PLA (compared with left atrial appendage). Triggered Ca2+ waves (TCWs) in HF PLA myocytes were particularly sensitive to acute ROS inhibition. Computational modeling confirmed a direct relationship between OS/CaMKII signaling and TCW generation. CaMKII phosphorylated Nav1.5 (CaMKII-p-Nav1.5 [S571]) was located preferentially at the intercalated disc (ID), being nearly absent at the lateral membrane. Furthermore, a decrease in ankyrin-G (AnkG) in HF led to patchy dropout of CaMKII-p-Nav1.5 at the ID, causing its distribution to become spatially heterogeneous; this corresponded to preferential slowing and inhomogeneity of conduction noted in the HF PLA. Computational modeling illustrated how conduction slowing (e.g., due to increase in CaMKII-p-Nav1.5) interacts with fibrosis to cause reentry in the PLA. We conclude that OS via CaMKII leads to substrate for triggered activity and reentry in HF PLA by mechanisms independent of but complementary to fibrosis.

Authors

Shin Yoo, Gary Aistrup, Yohannes Shiferaw, Jason Ng, Peter J. Mohler, Thomas J. Hund, Trent Waugh, Suzanne Browne, Georg Gussak, Mehul Gilani, Bradley P. Knight, Rod Passman, Jeffrey J. Goldberger, J. Andrew Wasserstrom, Rishi Arora

×

Figure 10

Schematic illustration of potential mechanisms by which OS leads to substrate for triggered activity and reentry in the HF PLA.

Options: View larger image (or click on image) Download as PowerPoint
Schematic illustration of potential mechanisms by which OS leads to subs...
Increase in ROS generation by NADPH oxidase (NOX2) and mitochondrial ROS results in enhanced oxidation of CaMKII in the HF PLA. Ox-CaMKII hyperphosphorylates downstream target molecules, including RyR2 and Nav1.5. At the cellular level, CaMKII-dependent phosphorylation of RyR2 leads to emergence of triggered Ca2+ waves, which predispose to afterdepolarizations (triggered activity). At the tissue level, CaMKII-dependent phosphorylation of Nav1.5 results in selective trafficking of the channel protein to the ID, with little or no trafficking to the lateral membrane (LM). An increase in the level of CaMKII-p-Nav1.5 (S571) would therefore be expected to decrease peak INa and lead to conduction slowing. Furthermore, a decrease in AnkG levels in HF leads to defective forward trafficking of CaMKII-p-Nav1.5 (S571) to the ID; this results in a patchy dropout of CaMKII-p-Nav1.5 (S571) and, therefore, in increased heterogeneity of expression of CaMKII-p-Nav1.5 (S571). The increased heterogeneity of expression of CaMKII-p-Nav1.5 (S571) promotes inhomogeneous conduction in the HF PLA. The conduction slowing and increased inhomogeneity of conduction caused by altered expression patterns of CaMKII-p-Nav1.5 (S571) leads to substrate for reentry. HF, heart failure; PLA, posterior left atrium; ID, intercalated disc.