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U937 Cell Necrosis Mediated by Peroxynitrite Is Not Caused by Depletion of ATP and Is Prevented by Arachidonate via an ATP-Dependent Mechanism

Istituto di Farmacologia e Farmacognosia (O.C., A.G., L.P.), and Istituto di Chimica Biologica "Giorgio Fornaini" (M.F.), Università Degli Studi di Urbino "Carlo Bo", Urbino, Italy

Exposure of U937 cells to an otherwise nontoxic concentration of peroxynitrite promotes a rapid necrotic response in the presence of pharmacological inhibitors of phospholipase A₂. A 12-fold higher concentration of the oxidant, in the absence of additional treatments, caused remarkably greater DNA single-strand breakage, delayed formation of H₂O₂, and depletion of reduced glutathione but an identical level of toxicity. Cell death was prevented in both circumstances by nanomolar levels of arachidonic acid or by cyclosporin A via mechanisms unrelated to elimination of the above effects and was causally linked to prevention of mitochondrial permeability transition. Treatment with a high dose of peroxynitrite for 30 min caused an approximately 40% decline in ATP, both in the absence and presence of arachidonate, whereas only a small, arachidonic acid-sensitive reduction of the ATP pool was detected in cells treated with the low dose of peroxynitrite and the phospholipase A₂ inhibitor. ATP-predepleted cells, however, were hypersensitive to peroxynitrite, and under these conditions, toxicity was not prevented by arachidonate. The above findings were reproduced in another promonocytic cell line, THP-1 cells. We concluded that the rapid necrotic response triggered by peroxynitrite in monocytes is mediated by a regulated process, not by ATP depletion, associated with reduced arachidonate availability. Supplementation of exogenous arachidonic acid always rescued cells via an ATP-dependent survival pathway.

Address correspondence to: Dr. Orazio Cantoni, Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo", Via S. Chiara, 27-61029 Urbino (PU), Italy. E-mail: cantoni{at}uniurb.it