Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 45, Issue 10, Pages 1487-1492Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2008.08.022
Keywords
4-Hydroxynonenal; MMP-2; Mitochondrial ROS; Akt/NF-kappa B pathways; Free radicals
Funding
- MRC program MOST/KOSEF [R13-2005-009]
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4-Hydroxynonenal (HNE) accumulates at atherosclerotic lesions, but its role in the progression of atherosclerosis is not clear. Considering the role of matrix metalloproteinases (MMP) in plaque destabilization, we investigated the mechanism by which HNE induces MMP production in vascular smooth Muscle Cells (VSMC) VSMC stimulated by HNE (1.0 mu M) produced enzymatically active MMP-2 with ail increased promoter activity, which was abolished by Mutation of the NF-kappa B binding site in the promoter region. The increased NF-kappa B activity with subsequent MMP-2 production by HNE was significantly attenuated by transfection with Akt siRNA as well as by pretreatment with the PI3K/Akt inhibitors LY294002 (10 PM) and SH-5 (1.0 mu M), The phosphorylation of Akt occurred as early as 5 min in VSMC exposed to HNE and was markedly attenuated by inhibition of mitochondrial reactive oxygen species (ROS). Furthermore the, impact of mitochondrial ROS on HNE-induced Akt phosphorylation with subsequent MMP-2 production was also demonstrated in mitochondrial function-deficient VSMC, as well as in cells transfected with manganese Superoxide dismutase. Taken together, these results Suggest that HNE enhances MMP-2 production in VSMC via mitochondrial ROS-mediated activation of the Akt/NF-kappa B signaling pathways. (C) 2008 Elsevier Inc. All Lights reserved.
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