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Induction of heme oxygenase 1 by moderately oxidized low-density lipoproteins in human vascular smooth muscle cells: role of mitogen-activated protein kinases and Nrf2

Anwar, A. A., Li, F. Y. L., Leake, D. S., Ishii, T., Mann, G. E. and Siow, R. C. M. (2005) Induction of heme oxygenase 1 by moderately oxidized low-density lipoproteins in human vascular smooth muscle cells: role of mitogen-activated protein kinases and Nrf2. Free Radical Biology and Medicine, 39 (2). pp. 227-236. ISSN 0891-5849

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To link to this article DOI: 10.1016/j.freeradbiomed.2005.03.012

Abstract/Summary

Oxidized low-density lipoproteins (LDL) play a central role in atherogenesis and induce expression of the antioxidant stress protein heme oxygenase 1 (HO-1). In the present study we investigated induction of HO-1 and adaptive increases in reduced glutathione (GSH) in human aortic smooth muscle cells (SMC) in response to moderately oxidized LDL (moxLDL, 100 mu g protein/ml, 24 h), a species containing high levels of lipid hydroperoxides. Expression and activity of HO-1 and GSH levels were elevated to a greater extent by moxLDL than highly oxidized LDL but unaffected by native or acetylated LDL. Inhibitors of protein kinase C (PKC) or mitogen-activated protein kinases (MAPK) p38(MAPK) and MEK or c-jun-NH2-terminal kinase (JNK) significantly attenuated induction of HO-1. Phosphorylation of p38(MAPK), extracellular signal-regulated kinase (ERK1/2), or JNK and nuclear translocation of the transcription factor Nrf2 were enhanced following acute exposure of SMC to rnoxLDL (100 mu g proteiri/ml, 1-2 h). Pretreatment of SMC with the antioxidant vitamin C (100 mu M, 24 h) attenuated the induction of HO-1 by moxLDL. Native and oxidized LDL did not alter basal levels of intracellular ATP, mitochondrial dehydrogenase activity, or expression of the lectin-like oxidized LDL receptor (LOX-1) in SMC. These findings demonstrate for the first time that activation of PKC, p38(MAPK), JNK, ERK1/2, and Nrf2 by oxidized LDL in human SMC leads to HO-1 induction, constituting an adaptive response against oxidative injury that can be ameliorated by vitamin C. (C) 2005 Elsevier Inc. All rights reserved.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Biological Sciences
Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
ID Code:10259
Uncontrolled Keywords:oxidized low-density lipoproteins, heme oxygenase, glutathione, mitogen-activated protein kinase, vitamin C, Nrf2, atherosclerosis, vascular smooth muscle, ANTIOXIDANT RESPONSE ELEMENT, VITAMIN-C PROTECTS, CARBON-MONOXIDE, GENE-EXPRESSION, ATHEROSCLEROTIC LESIONS, GLUTATHIONE SYNTHESIS, ENDOTHELIAL-CELLS, ALPHA-TOCOPHEROL, LDL, ACID

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