Tumor Necrosis Factor-α Regulates Heme Oxygenase-1 Expression in Endothelial Cells via the Phosphorylation of JNK/p38
Heme oxygenase-1 (HO-1), an enzyme degrading heme to carbon monoxide, iron, and biliverdin, has been recognized as playing a crucial role in cellular defense against stressful conditions, not only related to heme release. In the present study, the effects of TNF-a on the expression of heme oxygenase-1 (HO-1) in human aortic endothelial cells (HAECs) as well as the related mechanisms were investigated. 10 ng/mL TNF-α treatment significantly increased HO-1 expression after 6h, then a further increase at 12h and declined at 24h. Treatment with 2 ng/mL of TNF-a after 12 h resulted in a significant increase in HO-1 expression, which peaked at 10 ng/mL, then declined at 20 ng/mL. TNF-α induced HO-1 expression and then HO-1 expression reduced vascular cell adhesion molecule-1 (VCAM-1) expression. Phosphorylation studies of ERK1/2, JNK, and p38, three subgroups of mitogen-activated protein kinases (MAPKs) demonstrated TNF-α-induced ERK1/2, JNK, and p38 phosphorylation. The increase in HO-1 expression in response to TNF-α treatment was affected by pretreatment with SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), not with PD98059 (an ERK1/2 inhibitor). The expression of HO-1 was stronger in aortas of TNF-α-treated apo-E deficient mice when compared with control mice. These results suggest that low dose of TNF-α treatment notably induced HO-1 expression was mediated through JNK/p38 phosphorylation and may have a protective potential in cardiovascular diseases and inflammatory response through the regulation of HO-1 expression.
Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1088426Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 5405
 F.H. Bach, “Heme oxygenase-1: a therapeutic amplification funnel,” FASEB J., vol. 19, no. 10, pp. 1216–1219, 2005.
 T. Morita, “Heme oxygenase and atherosclerosis,” Arterioscler Thromb Vasc Biol., vol. 25, no. 9, pp. 1786–1795, 2005.
 K.A. Nath, J.J. Haggard, A.J. Croatt, J.P. Grande, K.D. Poss, J. Alam, “The indispensability of heme oxygenase-1 in protecting against acute heme protein- induced toxicity in vivo,” Am J Pathol., vol. 156, no. 5, pp. 1527–1535, 2000.
 S.W. Ryter, J. Alam, A.M. Choi, “Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications,” Physiol Rev., vol. 86, no. 2, pp. 583–650, 2006.
 L.E. Otterbein , F.H. Bach, J. Alam, M. Soares, H. Tao Lu, M. Wysk, R.J. Davis, R.A. Flavell, A.M. Choi, “Carbon monoxide has antiinflammatory effects involving the mitogen-activated protein kinase pathway,” Nat Med., vol. 6, no. 4, pp. 422–428, 2000.
 Y. Togane, T. Morita, M. Suematsu, Y. Ishimura, J. I. Yamazaki, S. Katayama, “Protective roles of endogenous carbon monoxide in neointimal development elicited by arterial injury,” Am J Physiol., vol. 278, no. 2, pp. 623–632, 2000.
 K.D. Poss, S. Tonegawa, “Heme oxygenase 1 is required for mammalian iron reutilization,” Proc Natl Acad Sci U S A., vol. 94, no. 20, pp. 10919–10924, 1997.
 R. Stocker, M.A. Perrella, “Heme oxygenase-1: a novel drug target for atherosclerotic diseases? ” Circulation., vol. 114, no. 20, pp. 2178– 2189, 2006.
 P. Wiesel, A.P.Patel, N. Difonzo, P.B. Marria, C.U. Sim, A. Pellacani, K. Maemura, B.W. Leblanc, K. Marino, C.M. Doerschuk, S.F. Yet, M.E. Lee, M.A. Perrella, “Endotoxin-induced mortality is related to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygenase-1-deficientmice,”Circulation., vol. 102, no. 24, pp. 3015–3022, 2000.
 S.F. Yet, M.A. Perrella, M.D. Layne, C.M. Hsieh, K. Maemura, L. Kobzik, P. Wiesel, H. Christou, S. Kourembanas, M.E. Lee, “Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice,” J Clin Invest., vol. 103, no. 8, pp. 23–29, 1999.
 K.Sato, J. Balla, L. Otterbein, R.N. Smith, S. Brouard, Y. Lin, E. Csizmadia, J. Sevigny, S.C. Robson, G.Vercellotti, A.M. Choi, F.H. Bach, M.P. Soares, “Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants,” J Immunol., vol. 166, no. 6, pp. 4185–4194, 2001.
 S. Mishra, T. Fujita, V.N. Lama, D. Nam, H. Liao, M. Okada, K. Minamoto, Y. Yoshikawa, H. Harada, D.J. Pinsky, “Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes,” Proc Natl Acad Sci U S A., vol. 103, no. 13, pp. 5191–5196, 2006.
 Baud, M. Karin,“Signal transduction by tumor necrosis factor and itsrelatives,” Trends Cell Biol., vol. 11, no. 9, pp. 372-377, 2001.
 I.A. van den Oever, H.G. Raterman, M.T. Nurmohamed, S. Simsek,“Endothelial dysfunction, inflammation, and apoptosis in diabetes mellitus,” Mediators Inflamm., vol. 2010, no. 2010, e792393, 2010.
 Y.M. Kim, H.O. Pae, J.E. Park, Y.C. Lee, J.M. Woo, N.H. Kim, Y.K. Choi, B.S. Lee, S.R. Kim, H.T. Chung,“Heme oxygenase in the regulation of vascular biology: from molecular mechanisms to therapeutic opportunities,” Antioxid. RedoxSignal., vol. 14, no. 1, pp. 137–167, 2011.
 I.T. Lee, S.F. Luo, C.W. Lee, S.W. Wang, C.C. Lin, C.C. Chang, Y.L. Chen, L.Y. Chau, C.M. Yang, “Overexpression of HO- 1 protects against TNF-alpha-mediated airway inflammation by down-regulation of TNFR1- dependent oxidative stress,” Am J Pathol., vol. 175, no. 2, pp. 519-532, 2009.
 Y.H. Chen, S.J. Lin, H.H. Ku, M.S. Shiao, F.Y. Lin, J.W. Chen, Y.L. Chen,“Salvianolic acid B attenuates VCAM-1 and ICAM-1 expression in TNF-alpha-treated human aortic endothelial cells,” J. Cell. Biochem., vol. 82, no. 3 , pp. 512-521, 2001.
 E.J. Park, Y.M. Kim, S.W. Park, H.J. Kim, J.H. Lee, D.U. Lee, K.C. Chang, “Induction of HO-1 through p38 MAPK/ Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPSactivated RAW 264.7 cells and CLP- induced septic mice,” Food Chem Toxicol., vol. 55, pp. 386-395, 2013.
 Speciale, S. Anwar, R. Canali , J. Chirafisi, A. Saija, F. Virgili, F. Cimino, “Cyanidin-3-O-glucoside counters the response to TNF-alpha of endothelial cells by activating Nrf2 pathway,” Mol. Nutr. Food Res., vol. 00, pp.1-9, 2013.