Differentiation-associated loss of ryanodine receptors: a strategy adopted by monocytes/macrophages to prevent the DNA single-strand breakage induced by peroxynitrite.
Monocytes/macrophages respond to peroxynitrite with the triggering of events leading to prevention of an otherwise prompt lethal response. This survival signaling regulated by molecules of the arachidonate cascade however presents a hypothetical critical limitation. In human promonocytic cell lines, peroxynitrite indeed promotes ryanodine receptor-derived Ca(2+)-dependent mitochondrial formation of H2O2, entirely responsible for the ensuing DNA strand scission. The occurrence of the same events in monocytes/macrophages at the inflammatory sites would therefore enhance the extent of DNA strand scission in viable cells, thereby increasing the rate of mutation and neoplastic transformation. The present study illustrates the details of a novel strategy based on a differentiation-associated loss of expression of ryanodine receptors. These cells simply do not accumulate mitochondrial Ca(2+) in response to peroxynitrite and therefore fail to generate superoxide/H2O2, thereby preserving the integrity of their DNA. We propose that an important component of the overall strategy adopted by monocytes/macrophages to survive to peroxynitrite, with no increased risk of neoplastic transformation, involves down-regulation of ryanodine receptor expression.
Guidarelli
Andrea
A
Istituto di Farmacologia e Farmacognosia Università degli Studi di Urbino Carlo Bo, Urbino 61029, Italy.
Cerioni
Liana
L
Fiorani
Mara
M
Cantoni
Orazio
O
D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000276:immunology*; D004272:DNA, Mitochondrial / Q000037:antagonists & inhibitors / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity*; D030421:Peroxynitrous Acid / Q000633:toxicity*; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology; D020298:U937 Cells
D004272:DNA, Mitochondrial; D004277:DNA, Single-Stranded; D016877:Oxidants; D019837:Ryanodine Receptor Calcium Release Channel; D030421:Peroxynitrous Acid; D006861:Hydrogen Peroxide; D002118:Calcium