Abstract
Abstract We have previously shown that dicarbonyl compounds, the major by-products of the glycation reaction, selectively induce heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) in rat aortic smooth muscle cells (RASMCs) by increasing intracellular peroxide levels. The mechanism by which dicarbonyls increase peroxide levels, thus inducing HB-EGF, was previously examined and found to be via the inactivation of glutathione peroxidase (GPx), a major peroxidase scavenging enzyme. In this study, we demonstrate that the nitric oxide (NO) donor, S -nitroso- N -acetyl- dl -penicillamine (SNAP), also induces HB-EGF in a dose- and time-dependent manner in RASMCs. The mechanism of induction involves the direct inactivation of GPx by NO, resulting in the accumulation of intracellular peroxides, which are able to act as a second messenger and activate c-Jun NH 2 -terminal kinase (JNK) and c-Jun/AP-1 signaling pathways. Furthermore, when RASMCs, incubated with SNAP, are also treated with antisense HB-EGF oligonucleotide, the cells enter apoptosis, suggesting that the induction of HB-EGF could be an adaptive response as an autocrine protective factor against apoptosis by NO in RASMCs. These data indicate that GPx undergoes inactivation under conditions of nitroxidative stress and glycoxidative stress, and that these changes are a common feature of various types of oxidative stress which may be associated with the modification of redox regulation and cellular function.
Published Version
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