X-ROS Signaling in Atrial Myocytes Produces Arrhythmogenic Ca2+ Waves

Abstract

Atrial myocytes undergo stretch during diastole as do ventricular myocytes. We have identified a novel mechanism that links cellular stretch in ventricular myocytes to the tuning of Ca2+ release from the sarcoplasmic reticulum (SR)(Prosser et al. Science 2011;333:1440-5). This mechanism, “X-ROS signaling”, depends on NOX2 (NADPH oxidase) to generate reactive oxygen species (ROS), which appears to oxidize ryanodine receptors (SR Ca2+ release channels) and increases their sensitivity to [Ca2+]i. Stretch mediates X-ROS signaling through microtubules, which appear to interact with NOX2 to enable it to generate ROS.We evaluated X-ROS signaling in murine and rabbit atrial myocytes. Ca2+ sparks and Ca2+ waves were recorded before and after stretch (10-20% of cell length). The frequency of Ca2+ release events (Ca2+ sparks and Ca2+ waves) increased in proportion to the amount of cell stretch (up to 20% of cell length). Higher single cell stretch (15-20% of cell length) produced arrhythmogenic Ca2+ waves, while lesser stretch leads to an increase in frequency of Ca2+ sparks. Stretch-induced Ca2+ waves were prevented by the NOX inhibitor DPI (Diphenyleneiodonium chloride). Interestingly, microtubule density was higher and protein expression levels were increased in murine atria compared to ventricles. Similarly, protein expression levels of the catalytic NOX2 subunit gp91phox were higher in atria compared to ventricles. Stretch-induced Ca2+ waves did not occur in rabbit cells treated with the NOX inhibitor DPI. Thus, X-ROS signaling is operative in atrial myocytes and can modulate Ca2+ signaling.