Abstract 13925: Reactive ?-Ketoaldehyde Products of Lipid Peroxidation Promote Protein Misfolding and Preamyloid Oligomer Formation in Experimental Atrial Fibrillation
Atrial fibrillation (AF) is a progressive arrhythmia, and the pathophysiology of AF-related remodeling remains poorly understood. In a cellular model of AF, we observed transcriptional upregulation for proteins implicated in amyloidosis, a process associated with protein misfolding and deposition. Pathological studies indicate that isolated atrial amyloidosis increases with aging and the development of AF in humans. Current evidence indicates that preamyloid oligomers (PAOs) are the primary cytotoxic species in the development of amyloidosis, while not detectable by Congo red staining. We hypothesized that rapid activation of atrial cells triggers protein misfolding and PAO production as a component of the cellular stress response. To investigate this hypothesis, both rapidly-paced and control, spontaneously-beating atrial HL-1 cells were probed with a unique antibody (A-11) recognizing a conformational epitope common to all PAOs. Using A-11, reproducible diffuse cytosolic immunostaining was present in rapidly-paced cells, which was absent in control unpaced cells or when IgG was substituted for A-11. Increasing evidence indicates that oxidative injury and inflammation can promote as AF susceptibility, as well as PAO formation and amyloidosis. Among the numerous injurious mediators generated by these processes, γ-ketoaldehydes are highly-reactive products that are formed via the isoprostane pathway of free radical mediated oxidative stress. Salicylamine (SA) is a novel compound that scavenges γ-ketoaldehydes, and it has also been shown to prevent PAO formation for amyloid β. To explore mechanisms of PAO formation in our experimental model, atrial HL-1 cells were subjected to rapid stimulation in the absence and presence of SA. In the presence of SA, both transcriptional remodeling (using quantitative real-time PCR to assay expression of Nppb and Hspa1a) and cytosolic PAO formation were significantly inhibited. These results demonstrate protein misfolding/PAO formation as a component of the atrial cell stress remodeling in response to rapid activation, and they provide a potential mechanistic link between oxidative stress, atrial cell injury, and AF susceptibility.
- © 2013 by American Heart Association, Inc.