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(Journal of Leukocyte Biology. 2001;70:87-95.)
© 2001 by Society for Leukocyte Biology

Nitric oxide induces murine thymocyte apoptosis by oxidative injury and a p53-dependent mechanism

Sherilyn A. Gordon^*, Walid Abou-Jaoude^*, Rosemary A. Hoffman^*, Susan A. McCarthy^*, Young-Myeong Kim^*, Xin Zhou^*, Xiao-Ru Zhang^*, Richard L. Simmons^*, Yue Chen^*, Laura Schall and Henri R. Ford^*

^* Department of Surgery, University of Pittsburgh School of Medicine,
Department of Biostatistics, Graduate School of Public Health, and
Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; and
Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon, Kangwondo, Korea

Correspondence: Dr. Henri R. Ford, Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail: FordH{at}chplink.chp.edu

Previously, we showed that NO induces thymocyte apoptosis via a caspase-1-dependent mechanism [¹ ]. In the present study, we investigated the role of heme oxygenase, catalase, bax, and p53 in this process. The NO donor, S-nitroso-N-acetyl penicillamine (SNAP), induced DNA fragmentation in thymocytes in a time- and concentration-dependent way. SNAP (100 µM) induced 50–60% apoptosis; higher doses did not increase the rate of apoptosis significantly. SNAP decreased catalase and heme iron (Fe) levels without affecting superoxide dismutase, glutathione, or total Fe stores in thymocytes. SNAP significantly increased the expression of heme oxygenase 1 (HSP-32), p53, and bax but not bcl-2. Treatment with the heme oxygenase inhibitor, tin protoporphyrin IX inhibited SNAP-induced thymocyte apoptosis. Furthermore, thymocytes from p53 null mice were resistant to NO-induced apoptosis. Our data suggest that NO may induce its cytotoxic effects on thymocytes by modulating heme oxygenase and catalase activity as well as up-regulating pro-apoptotic proteins p53 and bax.

Key Words: thymus • bax • heme oxygenase • catalase

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