Cell-to-cell communication plays a cardinal role in the biology of multicellular organisms. H 2 O 2 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 H 2 O 2 signals within minutes over long distances, measured in centimeters, in a monolayer of cardiomyocytes. Here we report that this long-distance H 2 O 2 signaling pathway is accompanied by enhanced accumulation of cytosolic H 2 O 2 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 H 2 O 2 signaling pathway that could play an important role in different inflammatory responses, wound responses/healing, cardiovascular disease, and/or other conditions.
Highlights: Wounding induces an H 2 O 2 cell-to-cell signal in a monolayer of cardiomyocytes. The cell-to-cell signal requires H 2 O 2 and O 2 · - 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.