Circulation Research. 2004;94:609-616
Published online before print January 29, 2004, doi: 10.1161/01.RES.0000119171.44657.45
Published online before print January 29, 2004, doi: 10.1161/01.RES.0000119171.44657.45
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© 2004 American Heart Association, Inc.
Molecular Medicine |
Role of Nrf2 in the Regulation of CD36 and Stress Protein Expression in Murine Macrophages
Activation by Oxidatively Modified LDL and 4-Hydroxynonenal
From the Institutes of Community Medicine (T.I.) and Basic Medical Sciences (K.I., H.U., M.Y.), University of Tsukuba, Tsukuba, Japan; Cell and Molecular Biology Research Division (D.S.L.), School of Animal and Microbial Sciences, University of Reading, UK; Centre for Cardiovascular Biology and Medicine (E.R., G.E.M.), GKT School of Biomedical Sciences, King’s College London, Guy’s Campus, London, UK.
Correspondence to Prof Tetsuro Ishii, Institute of Community Medicine, University of Tsukuba, Tsukuba 305-8575, Japan. E-mail teishii{at}md.tsukuba.ac.jp and Prof Giovanni E. Mann, Centre for Cardiovascular Biology and Medicine, GKT School of Biomedical Sciences, King’s College London, Guy’s Campus, London SE1 1UL, UK. E-mail giovanni.mann@kcl.ac.uk
CD36 is an important scavenger receptor mediating uptake of oxidized low-density lipoproteins (oxLDLs) and plays a key role in foam cell formation and the pathogenesis of atherosclerosis. We report the first evidence that the transcription factor Nrf2 is expressed in vascular smooth muscle cells, and demonstrate that oxLDLs cause nuclear accumulation of Nrf2 in murine macrophages, resulting in the activation of genes encoding CD36 and the stress proteins A170, heme oxygenase-1 (HO-1), and peroxiredoxin I (Prx I). 4-Hydroxy-2-nonenal (HNE), derived from lipid peroxidation, was one of the most effective activators of Nrf2. Using Nrf2-deficient macrophages, we established that Nrf2 partially regulates CD36 expression in response to oxLDLs, HNE, or the electrophilic agent diethylmaleate. In murine aortic smooth muscle cells, expressing negligible levels of CD36, both moderately and highly oxidized LDL caused only limited Nrf2 translocation and negligible increases in A170, HO-1, and Prx I expression. However, treatment of smooth muscle cells with HNE significantly enhanced nuclear accumulation of Nrf2 and increased A170, HO-1, and Prx I protein levels. Because PPAR-
can be activated by oxLDLs and controls expression of CD36 in macrophages, our results implicate Nrf2 as a second important transcription factor involved in the induction of the scavenger receptor CD36 and antioxidant stress genes in atherosclerosis.
Key Words: CD36 • Nrf2 • oxidized LDL • macrophages • vascular smooth muscle cells
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