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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2100.)
© 2005 American Heart Association, Inc.

Vascular Biology

-Lipoic Acid–Induced Heme Oxygenase-1 Expression Is Mediated by Nuclear Factor Erythroid 2-Related Factor 2 and p38 Mitogen-Activated Protein Kinase in Human Monocytic Cells

Richard M. Ogborne; Stuart A. Rushworth; Maria A. O’Connell

From MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, UK.

Correspondence to Maria O’Connell, PhD, MRC Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Rd, Cambridge, CB1 9NL, UK. E-mail maria.oconnell{at}mrc-hnr.cam.ac.uk

Objective— Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, plays a protective role in the vascular system. HO-1 induction inhibits cytokine production in macrophages. Antioxidants induce HO-1 expression in various cell types. -lipoic acid (ALA), a thiol-containing dietary antioxidant, exhibits protective effects in vascular disease and induces anti-inflammatory effects in monocytes. This study examined the effects of ALA on HO-1 expression in human monocytic cells.

Methods and Results— ALA time and dose-dependently induced HO-1 mRNA expression in THP-1 cells, with peak expression at 4 hours and returning to baseline by 24 hours. This correlated with an increase in HO-1 protein expression. ALA stimulated translocation of the transcription factor nuclear factor-erythroid 2–related factor 2 (Nrf2) into the nucleus and binding to a human HO-1 antioxidant response element (ARE) by 30 minutes. A dominant-negative Nrf2 inhibitor reduced ALA-induced HO-1 mRNA expression by 66%. Pretreatment with SB203580, a p38 mitogen-activated protein kinase inhibitor, reduced ALA-induced HO-1 mRNA expression by 75% and inhibited ALA-induced Nrf2 binding to the HO-1 ARE.

Conclusions— These results demonstrate that ALA induces HO-1 expression in THP-1 monocytic cells via Nrf2 and p38. Further studies are required to investigate whether the protective effects of ALA in monocytes are mediated by HO-1.

The effect of -lipoic acid (ALA) on heme oxygenase-1 (HO-1) expression was investigated in THP-1 monocytic cells. ALA induced HO-1 expression via Nrf2 and p38. Further studies are required to investigate whether the protective effects of ALA in monocytes are mediated by HO-1.

Key Words: -lipoic acid • monocyte • heme oxygenase-1 • Nrf2 • p38 MAPK

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