Propagation of a rapid cell-to-cell H2O2 signal over long distances in a monolayer of cardiomyocyte cells

Cell-to-cell communication plays a cardinal role in the biology of multicellular organisms. H2O2 is an important cell-to-cell signaling molecule involved in the response of mammalian cells to wounding and other stimuli. We previously identified a signaling pathway that transmits wound-induced cell-to-cell H2O2 signals within minutes over long distances, measured in centimeters, in a monolayer of cardiomyocytes. Here we report that this long-distance H2O2 signaling pathway is accompanied by enhanced accumulation of cytosolic H2O2 and altered redox state in cells along its path. We further show that it requires the production of superoxide, as well as the function of gap junctions, and that it is accompanied by changes in the abundance of hundreds of proteins in cells along its path. Our findings highlight the existence of a unique and rapid long-distance H2O2 signaling pathway that could play an important role in different inflammatory responses, wound responses/healing, cardiovascular disease, and/or other conditions. [Display omitted] •Wounding induces an H2O2 cell-to-cell signal in a monolayer of cardiomyocytes.•The cell-to-cell signal requires H2O2 and O2.- accumulation along its path.•The signal propagates over several centimeters changing the redox state of cells.•Changes in the abundance of hundreds of proteins accompanies the signal.•The cell-to-cell signal requires paracrine and juxtacrine signaling.