Gordon S A, Abou-Jaoude W, Hoffman R A, McCarthy S A, Kim Y M, Zhou X, Zhang X R, Simmons R L, Chen Y, Schall L, Ford H R
Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania, USA.
J Leukoc Biol. 2001 Jul;70(1):87-95.
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 microM) 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.
此前，我们发现一氧化氮（NO）通过一种依赖半胱天冬酶-1的机制诱导胸腺细胞凋亡[(1)]。在本研究中，我们调查了血红素加氧酶、过氧化氢酶、bax和p53在此过程中的作用。NO供体S-亚硝基-N-乙酰青霉胺（SNAP）以时间和浓度依赖的方式诱导胸腺细胞中的DNA片段化。SNAP（100微摩尔）诱导50%-60%的细胞凋亡；更高剂量并未显著增加细胞凋亡率。SNAP降低了过氧化氢酶和血红素铁（Fe）水平，但不影响胸腺细胞中的超氧化物歧化酶、谷胱甘肽或总铁储备。SNAP显著增加了血红素加氧酶1（HSP-32）、p53和bax的表达，但不增加bcl-2的表达。用血红素加氧酶抑制剂锡原卟啉IX处理可抑制SNAP诱导的胸腺细胞凋亡。此外，来自p53基因敲除小鼠的胸腺细胞对NO诱导的凋亡具有抗性。我们的数据表明，NO可能通过调节血红素加氧酶和过氧化氢酶活性以及上调促凋亡蛋白p53和bax来诱导其对胸腺细胞的细胞毒性作用。
