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.