Stretch-Dependent Sub-Cellular Ca2+ Signaling in Atrial Myocytes

Abstract

Atrial fibrillation (AF) is a multifactorial disease whose underlying mechanisms are still incompletely understood. Atrial myocytes undergo similar stretch during diastolic filling as ventricular myocytes and acute atrial stretch can induce AF. Our group recently identified a novel mechanism linking cellular stretch to the tuning of Ca2+ release from the sarcoplasmic reticulum (SR) in ventricular myocytes (Prosser et al. Science 201;333:1440-5). This mechanism, “X-ROS signaling”, depends on NOX2 (NADPH oxidase) to generate reactive oxygen species (ROS), which oxidizes the local RyR2 Ca2+ release channels of the SR and increases their Ca2+ sensitivity. Stretch mediates X-ROS signaling through microtubules, which interact with NOX2 located in transverse tubules and the surface sarcolemmal membranes.Interestingly, in atrial myocytes from AF patients both increased ROS levels and arrhythmogenic Ca2+ signaling instability are present. We evaluated the effect of acute and repeated stretch on sub-cellular Ca2+ sparks in murine atrial myocytes (C57/B6) with instrumentation (WPI, Sarasota, FL) and methods of Prosser et al. (2011). Ca2+ sparks were recorded before and after acute and repeated stretch (8% of cell length). Here, we report an increase in stretch-dependent Ca2+ spark frequency in single murine atrial myocytes. Thus, stretch-dependent Ca2+ release mechanisms are also operative in atrial myocytes and likely to play a role in Ca2+ dependent arrhythmias like AF. Our ongoing work will interrogate the components of the X-ROS pathway to determine the relative contribution of this pathway in atrial myocytes.