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(Circulation Research. 2008;103:e1.)
© 2008 American Heart Association, Inc.

UltraRapid Communication

Nrf2 Regulates Antioxidant Gene Expression Evoked by Oxidized Phospholipids in Endothelial Cells and Murine Arteries In Vivo

Henna-Kaisa Jyrkkänen^*, Emilia Kansanen^*, Matias Inkala, Annukka M. Kivelä, Hanna Hurttila, Suvi E. Heinonen, Gundars Goldsteins, Suvi Jauhiainen, Satu Tiainen, Harri Makkonen, Olga Oskolkova, Taras Afonyushkin, Jari Koistinaho, Masayuki Yamamoto, Valery N. Bochkov, Seppo Ylä-Herttuala, Anna-Liisa Levonen

From the Department of Biotechnology and Molecular Medicine (H.-K.J., E.K., M.I., A.M.K., H.H., S.E.H., S.J., S.T., S.Y.-H., A.-L.L.) and Department of Neurobiology (G.G., J.K.), A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland; Institute of Biomedicine, Medical Biochemistry (H.M.), Faculty of Medicine, University of Kuopio, Finland; Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency–Exploratory Research for Advanced Technology Environmental Response Project (M.Y.), University of Tsukuba, Japan; Department of Medical Biochemistry (M.Y.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Vascular Biology and Thrombosis Research (O.O., T.A., V.N.B.), Medical University of Vienna, Austria; and Gene Therapy Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.

Correspondence to Anna-Liisa Levonen, MD, PhD, Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. E-mail Anna-Liisa.Levonen{at}uku.fi

Besides their well-characterized proinflammatory and proatherogenic effects, oxidized phospholipids, such as oxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphocholine) have been shown to have beneficial responses in vascular cells via induction of antioxidant enzymes such as heme oxygenase-1. We therefore hypothesized that oxPAPC could evoke a general cytoprotective response via activation of antioxidative transcription factor Nrf2. Here, we show that oxPAPC increases nuclear accumulation of Nrf2. Using the small interfering RNA approach, we demonstrate that Nrf2 is critical in mediating the induction of glutamate-cysteine ligase modifier subunit (GCLM) and NAD(P)H quinone oxidoreductase-1 (NQO1) by oxPAPC in human endothelial cells, whereas the contribution to the induction of heme oxygenase-1 was less significant. The induction of GCLM and NQO1 was attenuated by reduction of electrophilic groups with sodium borohydrate, as well as treatment with thiol antioxidant N-acetylcysteine, suggesting that the thiol reactivity of oxPAPC is largely mediating its effect on Nrf2-responsive genes. Moreover, we show that oxidized phospholipid having a highly electrophilic isoprostane ring in its sn-2 position is a potent inducer of Nrf2 target genes. Finally, we demonstrate that the oxPAPC-inducible expression of heme oxygenase-1, GCLM, and NQO1 is lower in Nrf2-null than wild-type mouse carotid arteries in vivo. We suggest that the activation of Nrf2 by oxidized phospholipids provides a mechanism by which their deleterious effects are limited in the vasculature.

Key Words: antioxidant response element • electrophile response element • Nrf2 • oxidized phospholipids

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