期刊
FASEB JOURNAL
卷 20, 期 1, 页码 518-+出版社
WILEY
DOI: 10.1096/fj.05-4875fje
关键词
glutathione; oxidized low-density lipoproteins; thiol
资金
- DIVISION OF HEART AND VASCULAR DISEASES [N01HV028178] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL081587, P01HL068758] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG012993, R01AG027080] Funding Source: NIH RePORTER
- NHLBI NIH HHS [P01-HL-81587, HL-68758, N01-HV-28178] Funding Source: Medline
- NIA NIH HHS [AG-27080, P01 AG 12993] Funding Source: Medline
The highly reactive species, peroxynitrite, is produced in endothelial cells in pathological states in which the production of superoxide anion and NO is increased. Here, we show that peroxynitrite added exogenously or generated endogenously in response to exposure to an NO donor or oxidized low-density lipoproteins (oxLDL) increases p21ras activity in bovine aortic endothelial cells. The activation is not dependent on upstream elements but rather is due to direct targeting of p21ras by reversible S-glutathiolation of cysteine thiols as demonstrated by biotin-labeling techniques. The time course of p21ras S-glutathiolation following peroxynitrite corresponds to the increase in its Raf-1 binding activity and translocation to the membrane. Moreover, p21ras S-glutathiolation and activation can be reversed by dithiothreitol, confirming the importance of a disulfide bond. S-glutathiolation also promoted guanine nucleotide exchange of recombinant p21ras. In addition, the oxidant-induced activation of Mek/Erk and PI3 kinase/Akt was abrogated by dominant-negative and Cys-118p21ras mutants, and the latter also prevented S-glutathiolation of p21ras. These results indicate that peroxynitrite arising from NO donors or pathological stimuli such as oxLDL triggers direct S-glutathiolation of p21ras Cys-118, which increases p21ras activity and mediates downstream signaling.
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