Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal.
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-gamma 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.
Ishii
Tetsuro
T
Institute of Community Medicine, University of Tsukuba, Japan. teishii@md.tsukuba.ac.jp
Itoh
Ken
K
Ruiz
Emilio
E
Leake
David S
DS
Unoki
Hiroyuki
H
Yamamoto
Masayuki
M
Mann
Giovanni E
GE
D048868:Adaptor Proteins, Signal Transducing; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001161:Arteriosclerosis / Q000209:etiology / Q000628:therapy; D018955:CD36 Antigens / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008298:Maleates / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2; D018384:Oxidative Stress; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics; D051116:Receptors, Scavenger; D000077154:Rosiglitazone; D000071456:Sequestosome-1 Protein; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D000447:Aldehydes; D018955:CD36 Antigens; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D018398:Homeodomain Proteins; D008077:Lipoproteins, LDL; D008298:Maleates; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C489936:Prrx1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D000077154:Rosiglitazone; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C014476:diethyl maleate; C027576:4-hydroxy-2-nonenal