PO-01-170 PHARMACOLOGICAL AND GENE-THERAPY BASED INHIBITION OF NOX2-GENERATED ROS ATTENUATES DISRUPTION OF MICROTUBULE NETWORK AND EMERGENCE OF TRIGGERED CA WAVES IN ATRIAL MYOCYTES AND IN CHRONIC AF CANINE MODEL

Recent research indicate an important role for derailed proteostasis in atrial fibrillation (AF). Major pathways of include disruption microtubule network (MTN). Experimental and clinical studies have documented a significant contribution histone deactylase 6 (HDAC6) mediated MTN. Another major causative factor AF is excessive oxidative stress (OS). However, clear connection MTN with OS not known myocytes chronic model AF. In particular, it remains elusive whether by NOX2-generated reactive oxygen species (ROS) contributes to the emergence triggered Ca2+ waves (TCWs), which can cause membrane depolarization promote early-afterdepolarization (EAD). To establish between isolated canine myocardium Normal were from 4 dogs pre-incubated Colchicine (a disruptor) H2O2. While myocytes, loaded sensitive dye, paced at different cycle lengths (1000ms 200ms), line-scan confocal imaging performed presence gp91-tat NOX2 inhibitor) TSA HDAC6 inhibitor). same cells, was examined Immunofluorescence. determine organization AF, immunohischemistry tissue sections 3 normal animals, control rapid pacing (RAP) NOX2-shRNA injected RAP animals. treated- acute application attenuated (a) generation TCWs (b). Similarly, H2O2 pretreated (data shown). Notably, while distinctive abolished induced sections, there attenuation expected decrease (c). Inhibition either shRNA injection or inhibitor as well associated TCWs. Identifying only sheds light on molecular mechanisms underlying but also may allow develop novel therapeutic approach