Ligands of Peroxisome Proliferator-activated Receptor Inhibit Homocysteine induced DNA Methylation of Inducible Nitric Oxide Synthase Gene
Corresponding Author
Yideng Jiang
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
*Corresponding Author: Tel, 86-951-4083421; Fax, 86-951-4081245; E-mail, [email protected]Search for more papers by this authorJianzhong ZHANG
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
Search for more papers by this authorJiantuan XIONG
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
Search for more papers by this authorJun CAO
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
Search for more papers by this authorGuizhong LI
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
Search for more papers by this authorShuren WANG
Department of Pathophysiology, West China College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu 610041, China
Search for more papers by this authorCorresponding Author
Yideng Jiang
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
*Corresponding Author: Tel, 86-951-4083421; Fax, 86-951-4081245; E-mail, [email protected]Search for more papers by this authorJianzhong ZHANG
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
Search for more papers by this authorJiantuan XIONG
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
Search for more papers by this authorJun CAO
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
Search for more papers by this authorGuizhong LI
Department of Pathology, Ningxia Medical College, Yinchuan 750004, China
Search for more papers by this authorShuren WANG
Department of Pathophysiology, West China College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu 610041, China
Search for more papers by this authorThis work was supported by a grant form the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20050610050)
Abstract
Homocysteine (Hcy) is a risk factor for atherosclerosis. It is generally accepted that inducible nitric oxide synthase (iNOS) is a key enzyme in the regulation of vascular disease. The aim of the present study is to investigate the effects of peroxisome proliferator-activated receptor ligands on iNOS in the presence of Hcy in human monocytes. Foam cells, induced by oxidize low density lipoprotein (ox-LDL) and phorbol myristate acetate (PMA) in the presence of different concentrations of Hcy, clofibrate and pioglitazone in human monocytes for 4 d, were examined by oil red O staining. The activity of iNOS was detected by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis. The capability of DNA methylation was measured by assaying endogenous C5 DNA methyltransferase (C5MTase) activity, and the iNOS promoter methylation level was determined by quantitative MethyLight assays. The results indicated that Hcy increased the activity of C5MTase and the level of iNOS gene DNA methylation, resulting in a decrease of iNOS expression. Clofibrate and pioglitazone could antagonize the Hcy effect on iNOS expression through DNA methylation, resulting in attenuation of iNOS transcription. These findings suggested that Hcy decreased the expression of iNOS by elevating iNOS DNA methylation levels, which can repress the transcription of some genes. Peroxisome proliferator-activated receptor α/γ ligands can down-regulate iNOS DNA methylation, and could be useful for preventing Hcy-induced atherosclerosis by repressing iNOS expression.
References
- 1 Turhan H, Erbay AR, Yasar AS, Bicer A, Sahin O, Basar N, Yetkin E. Plasma homocysteine levels in patients with isolated coronary artery ectasia. Int J Cardiol 2005, 104: 158–162.
- 2 Van Eck M, Van Dijk KW, Herijgers N, Hofker MH, Groot PH, Van Berkel TJ. Essential role for the (hepatic) LDL recept or in macrophage apolipoprotein E-induced reduction in serum cholesterol levels and atherosclerosis. Atherosclerosis 2001, 154: 103–112.
- 3 Yla-Herttuala S, Nikkari T, Hirvonen J, Laaksonen H, Mottonen M, Pesonen E, Raekallio J et al. Biochemical composition of coronary arteries in Finnish children. Arteriosclerosis 1986, 6: 230–236.
- 4 Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer 2004, 45: 143–153.
- 5 Greger V, Passarge E, Hopping W, Messmer E, Horsthemke B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet 1989, 83: 155–158.
- 6 Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002, 3: 415–428.
- 7 Mayer W, Niveleau A, Walter J, Fundele R, Haaf T. Demethylation of the zygotic paternal genome. Nature 2000, 403: 501–502.
- 8 Torra IP, Chinetti G, Duval C, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors: From transcriptional control to clinical practice. Curr Opin Lipidol 2001, 12: 245–254.
- 9 Kirkeboen KA, Strand OA. The role of nitric oxide in sepsis-an overview. Acta Anaesthesiol Scand 1999, 43: 275–288.
- 10 Ortega Mateo A, Amaya Aleixandre de Artinano M. Nitric oxide reactivity and mechanisms involved in its biological effects. Pharmacol Res 2000, 42: 421–427.
- 11 Chui PC, Guan HP, Lehrke M, Lazar MA. PPARgamma regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1. J Clin Invest 2005, 115: 2244–2256.
- 12 Escames G, Lopez LC, Tapias V, Utrilla P, Reiter RJ, Hitos AB, Leon J et al. Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice. J Pineal Res 2006, 40: 71–78.
- 13 Van Den Brandhof WE, Haks K, Schouten EG, Verhoef P. The relation between plasma cysteine, plasma homocysteine and coronary atherosclerosis. Atherosclerosis 2001, 157: 403–409.
- 14 Hattori N, Abe T, Hattori N, Suzuki M, Matsuyama T, Yoshida S, Li E, Shiota K. Preference of DNA methyltransferases for CpG islands in mouse embryonic stem cells. Genome Res 2004, 14: 1733–1740.
- 15 Aratani S, Fujii R, Oishi T, Fujita H, Amano T, Ohshima T, Hagiwara M et al. Dual roles of RNA helicase A in CREB-dependent transcription. Mol Cell Biol 2001, 21: 4460–4469.
- 16 Sekimata M, Takahashi A, Murakami-Sekimata A, Homma Y. Involvement of a novel zinc finger protein, MIZF, in transcriptional repression by interacting with a methyl-CpG-binding protein, MBD2. J Biol Chem 2001, 276: 42632–42638.
- 17 Bibikova M, Lin Z, Zhou L, Chudin E, Garcia EW, Wu B, Doucet D et al. High-throughput DNA methylation profiling using universal bead arrays. Genome Res 2006, 16: 383–393.
- 18 Ying AK, Hassanain HH, Roos CM, Smiraglia DJ, Issa JJ, Michler RE, Caligiuri M et al. Methylation of the estrogen receptor-alpha gene promoter is selectively increased in proliferating human aortic smooth muscle cells. Cardiovasc Res 2000, 46: 172–179.
- 19 Weisenberger DJ, Campan M, Long TI, Kim M, Woods C, Fiala E, Ehrlich M et al. Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 2005, 33: 6823–6836.
- 20 Fong IW. Emerging relations between infectious diseases and coronary artery disease and atherosclerosis. CMAJ 2000, 163: 49–56.
- 21
De Boer OJ,
Van Der Wal AC,
Becker AE.
Atherosclerosis, inflammation, and infection.
J Pathol
2000, 190: 237–243.
10.1002/(SICI)1096-9896(200002)190:3<237::AID-PATH541>3.0.CO;2-N CAS PubMed Web of Science® Google Scholar
- 22 Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer 2004, 4: 143–153.
- 23 Greger V, Passarge E, Hopping W, Messmer E, Horsthemke B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet 1989, 83: 155–158.
- 24 Hiltunen MO, Turunen MP, Hakkinen TP, Rutanen J, Hedman M, Makinen K, Turunen AM et al. DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. Vasc Med 2002, 7: 5–11.
- 25 Huang Y, Peng K, Su J, Huang Y, Xu Y, Wang S. Different effects of homocysteine and oxidized low density lipoprotein on methylation status in the promoter region of the estrogen receptor alpha gene. Acta Biochim Biophys Sin 2007, 39: 19–26.
- 26 Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985, 37: 1–31.
- 27 Woo KS, Chook P, Lolin YI, Cheung AS, Chan LT, Sun YY, Sanderson JE et al. Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation 1997, 96: 2542–2544.
- 28 Mainlow MR. Hyperhomocyst(e)inemia. A common and easily reversible risk factor for occlusive atherosclerosis. Circulation 1990, 81: 2004–2006.
- 29 Refsum H, Ueland PM. Recent data are not in conflict with homocysteine as a cardiovascular risk factor. Curr Opin Lipidol 1998, 9: 533–539.
- 30 Poddar R, Sivasubramanian N, DiBello PM, Robinson K, Jacobsen DW. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: Implications for vascular disease. Circulation 2001, 103: 2717–2723.
- 31 Sung FL, Slow YL, Wang G, Lynn EG, Karmin O. Homocysteine stimulates the expression of monocyte chemoattractant protein-1 in endothelial cells leading to enhanced monocyte chemotaxis. Mol Cell Biochem 2001, 216: 121–128.
- 32 Zhang Q, Zeng X, Guo J, Wang X. Effects of homocysteine on murine splenic B lymphocyte proliferation and its signal transduction mechanism. Cardiovasc Res 2001, 52: 328–336.
- 33 Zhang Q, Zeng X, Guo J, Wang X. Oxidant stress mechanism of homocysteine potentiating conA-induced proliferation in murine T lymphocytes. Cardiovasc Res 2002, 53: 1035–1042.
- 34 Holven KB, Aukrust P, Holm T, Ose L, Nenseter MS. Folic acid treatment reduces chemokine release from peripheral blood mononuclear cells in hyperhomocysteinemic subjects. Arterioscler Thromb Vasc Biol 2002, 22: 699–703.
- 35 Apostolopoulos J, Davenport P, Tipping PG. Interleukin-8 production by macrophages from atheromatous plaques. Arterioscler Thromb Vasc Biol 1996, 16: 1007–1012.
- 36 Kim YI, Christman JK, Fleet JC, Cravo ML, Salomon RN, Smith D, Ordovas J et al. Moderate folate deficiency does not cause global hypomethylation of he pat ic a nd c olonic DNA or c-myc-specific hypomethylation of colonic DNA in rats. Am J Clin Nutr 1995, 61: 1083–1090.
- 37 Blanchette J, Jaramillo M, Olivier M. Signalling events involved in inter-feron-gamma-inducible macrophage nitric oxide generation. Immunology 2003, 108: 513–522.
- 38 Gao J, Morrison DC, Parmely TJ, Russell SW, Murphy WJ. An interferon-gamma-activated site (GAS) is necessary for full expression of the mouse iNOS gene in response to interferon-gamma and lipopolysaccharide. J Biol Chem 1997, 272: 1226–1230.
- 39 Gatto L, Berlato C, Poli V, Tininini S, Kinjyo I, Yoshimura A, Cassatella MA et al. Analysis of SOCS-3 promoter responses to interferon gamma. J Biol Chem 2004, 279: 13746–13754.
- 40 Woo CW, Cheung F, Chan VW, Siow YL, Karmin O. Homocysteine stimulates inducible nitric oxide synthase expression in macrophages: Antagonizing effect of ginkgolides and bilobalide. Mol Cell Biochem 2003, 243: 37–47.
- 41 Moore KJ, Rosen ED, Fitzgerald ML, Randow F, Andersson LP, Altshuler D, Milstone DS et al. The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat Med 2001, 7: 41–47.
- 42 Hunt MJ, Tyagi SC. Peroxisome proliferators compete and ameliorate Hcymediated endocardial endothelial cell activation. Am J Physiol Cell Physiol 2002, 283: 1073–1079.
- 43 Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 1992, 11: 1921–1929.
