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As the Worm Squirms
Restoration of oxygen supply to cells that have been deprived of oxygen actually causes further damage to cells and tissues. Such responses, known as reperfusion injury, contribute to the deadly effects of heart attacks and strokes in humans. Lack of oxygen is sensed directly by a prolyl hydroxylase known as EGL-9 in worms and EGLN2 in mammals. Inhibition of EGL-9 can reduce damage caused by reperfusion of tissues with oxygen, but how such beneficial effects are mediated is not clear. Ma et al. (p. 554, published online 27 June) used a genetic screen in the nematode Caenorhabditis elegans, which has a behavioral response to reoxygenation in which the animals increase their movement, to find factors that interact with EGL-9. They identified the cytochrome p450 oxygenase CYP-13A12 as such a factor. Some cytochrome p450 enzymes act on polyunsaturated fatty acids to make cellular signaling molecules known as eicosanoids. The effects of CYP-13A23 were mediated by eicosanoids. Because the regulatory pathways involved appear to be evolutionarily conserved, the results may aid understanding and management of reperfusion injury in humans.
Abstract
Oxygen deprivation followed by reoxygenation causes pathological responses in many disorders, including ischemic stroke, heart attacks, and reperfusion injury. Key aspects of ischemia-reperfusion can be modeled by a Caenorhabditis elegans behavior, the O2-ON response, which is suppressed by hypoxic preconditioning or inactivation of the O2-sensing HIF (hypoxia-inducible factor) hydroxylase EGL-9. From a genetic screen, we found that the cytochrome P450 oxygenase CYP-13A12 acts in response to the EGL-9–HIF-1 pathway to facilitate the O2-ON response. CYP-13A12 promotes oxidation of polyunsaturated fatty acids into eicosanoids, signaling molecules that can strongly affect inflammatory pain and ischemia-reperfusion injury responses in mammals. We propose that roles of the EGL-9–HIF-1 pathway and cytochrome P450 in controlling responses to reoxygenation after anoxia are evolutionarily conserved.
