Hmg Co-A Reductase Inhibitors Attenuate Tachycardia-Induced Oxidative Stress and Cellular Remodeling in Hl-1 Atrial Myocytes

Background and Aim of the study: Atrial fibrillation (AF) is the most common sustained clinical tachyarrhythmia. All the electrical, contractile, and structural remodeling are important synergistic contributors to the AF substrate. Structural remodeling and oxidative stress occur in the atria of AF patients, but the pathogenic mechanisms underlying the creation of this particular tissue microenvironment are still debated. In vitro and in vivo atrial tachycardia causes ultrastructural remodeling in myocytes. This study will determine whether oxidative stress contributes to atrial tachycardia-induced cellular remodeling and the potential benefit of statins in attenuating this remodeling in an in vitro model. We will use HL-1 atria myocytes subjected to electrical field stimulation at different frequency. Oxidative stress, calcium load, mitochondria membrane potential and myolysis will be assessed by dichlorofuorescin, flou-4, tetra- methyrhodamine, and myosin heavy chain immunofluorescence respectively with confocal microscopy. Protein level will be measured by immunoblot. NADPH oxidase-driven oxidative stress was assessed using ex vivo Langendorff rat heart subjected to rapid pacing. All the experiment will be conducted with and without pretreatment with statins or inhibitors. In this project, we expect to find rapid HL-1 myocyte pacing increases calcium load, more depolarized mitochondria membrane potential and induces oxidative stress. Rapid pacing also causes marked structural remodeling: myolysis. Reactive oxygen species scavenger (NAC), mitochondrial translocator protein inhibitor, inhibitors and SiRNA of NADPH oxidases may attenuate both rapid pacing-induced oxidative stress and myolysis. Ex vivo study may find the association of oxidative stress and rapid pacing.

Project ID:PC10007-1179
External Project ID:NSC100-2314-B182A-084