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Isolevuglandins, a novel class of isoprostenoid derivatives, function as integrated sensors of oxidant stress and are generated by myeloperoxidase in vivo

EUGENIA POLIAKOV, MARIE-LUISE BRENNAN^*,, JENNIFER MACPHERSON^*, RENLIANG ZHANG^*,, WEI SHA, LAURA NARINE^*, ROBERT G. SALOMON and STANLEY L. HAZEN^*,,,1

Department of Chemistry, Case Western Reserve University, Departments of
^* Cell Biology and
Cardiovascular Medicine, Cleveland Clinic Foundation, and
Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, Ohio, USA

¹ Correspondence: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, NC-10, Cleveland, OH 44195, USA. E-mail: hazens{at}ccf.org

Isolevuglandins (isoLGs) are a family of reactive -ketoaldehydes generated by free radical oxidation of arachidonate-containing lipids through the isoprostane pathway. Elevated plasma levels of isoLG protein adducts are observed in subjects with atherosclerosis compared with age/gender-matched controls. However, mechanisms for the generation of isoLGs in vivo are not established. Here we show that free radical-induced peroxidation promoted by the myeloperoxidase (MPO)/H₂O₂ system of leukocytes serves as one mechanism for the generation of isoLGs in vivo. Using a Candida sepsis model of inflammation, we demonstrate 3.5- and 2.7-fold increases in iso[4]LGE₂ and isoLGE₂ adducts of plasma proteins after pathogen exposure in wild-type mice. Plasma levels of F₂ isoprostanes were not significantly increased after pathogen challenge in this model. MPO knockout mice demonstrated significant reductions (34%, P=0.003) in plasma levels of iso[4]LGE₂ protein adducts after pathogen challenge compared with wild-type mice. Mass spectrometry and immunochemical methods demonstrate MPO-dependent formation of iso[4]LGE₂ and isoLGE₂ phospholipids and their corresponding isoLG protein adducts in model systems. The present studies thus identify MPO as one pathway for generation of isoLGs in vivo. They also suggest that long-lived protein isoLG adducts may serve as an alternative integrated sensor of oxidant stress in vivo.—Poliakov, E., Brennan, M.-L., MacPherson, J., Zhang, R., Sha, W., Narine, L., Salomon, R. G., Hazen, S. L. Isolevuglandins, a novel class of isoprostenoid derivatives, function as integrated sensors of oxidant stress and are generated by myeloperoxidase in vivo.

Key Words: isoprostane • myeloperoxidase • isolevuglandin • oxidant stress

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