Stretch Dependent XROS Signaling: Rapid Mechanotransduction in Heart

Abstract

Control of cardiac Ca2+ release is critical for the regulation of contraction and maintenance of electrical activity. We have recently identified a provocative new signaling pathway, termed “X-ROS” signaling, that regulates normal Ca2+ release in healthy heart cells, but which may drive pathologic Ca2+ release in disease (Prosser et al., Science, 2011). The novel signaling arises from the physiological lengthening of heart cells (i.e. a stretch), such that occurs during diastolic filling. This stretch triggers the generation of reactive oxygen species (ROS) by the enzyme complex NADPH oxidase-2 (NOX2). NOX2 is found at the surface sarcolemmal membrane and in the transverse tubules of heart cells, closely opposed to Ca2+ release channels (ryanodine receptors, or RyR2s) in the junctional sarcoplasmic reticulum. A stretch-dependent process activates NOX2 production of ROS (“X-ROS” signaling), which reversibly oxidizes nearby RyR2s. X-ROS oxidation “tunes” the sensitivity of the RyR2s, resulting in an increase in the Ca2+ spark rate and enhancement of Ca2+ signaling. This process is defective in the fatal muscle disease Duchenne Muscular Dystrophy (DMD), and likely contributes to abnormal Ca2+ signaling in DMD.Our recent results suggest that during a sustained stretch of a cardiomyocyte, there is a rapid, yet transient (∼15s) elevation of ROS production that subsides over the duration of stretch. However, during repetitive cyclical stretch, such as occurs during the cardiac cycle, a new level of steady-state ROS production is achieved and maintained. This suggests that the level of steady state ROS generation in the cell may be graded by diastolic length, or pre-load. This finding has key implications for the role of redox signaling and oxidative stress in cardiac patho/physiology. Current work is aimed at investigating how this process operates in the intact, beating heart.