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S-adenosyl methionine prevents endothelial dysfunction by inducing heme oxygenase-1 in vascular endothelial cells

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Molecules and Cells

Abstract

S-adenosyl methionine (SAM) is a key intermediate in the metabolism of sulfur amino acids and is a major methyl donor in the cell. Although the low plasma level of SAM has been associated with atherosclerosis, the effect of SAM administration on atherosclerosis is not known. Endothelial dysfunction is an early prerequisite for atherosclerosis. This study was undertaken to investigate the possible preventive effect of SAM on endothelial dysfunction and the molecular mechanism of its action. SAM treatment prevented endothelial dysfunction in high fat diet (HFD)-fed rats. In cultured human aortic endothelial cells, linoleic acid (LA) increased and SAM decreased cell apoptosis and endoplasmic reticulum stress. Both LA and SAM increased heme oxygenase-1 (HO-1) expression in an NF-E2-related factor 2-dependent manner. However, knockdown of HO-1 reversed only the SAM-induced preventive effect of cell apoptosis. The LA-induced HO-1 expression was dependent on PPARα, whereas SAM induced HO-1 in a PPAR-independent manner. These data demonstrate that SAM treatment prevents endothelial dysfunction in HFDfed animals by inducing HO-1 in vascular endothelial cells. In cultured endothelial cells, SAM-induced HO-1 was responsible for the observed prevention of cell apoptosis. We propose that SAM treatment may represent a new therapeutic strategy for atherosclerosis.

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References

  • Alam, J., and Cook, J.L. (2007). How many transcription factors does it take to turn on the heme oxygenase-1 gene? Am. J. Respir. Cell Mol. Biol. 36, 166–174.

    Article  PubMed  CAS  Google Scholar 

  • Austin, R.C., Lentz, S.R., and Werstuck, G.H. (2004). Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. 11, S56–S64.

    Article  PubMed  CAS  Google Scholar 

  • Bao, X.M., Wu, C.F., and Lu, G.P. (2010). Atorvastatin inhibits homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells. Acta Pharmacol. Sin. 31, 476–484.

    Article  PubMed  CAS  Google Scholar 

  • Bianchi, A., Becuwe, P., Franck, P., and Dauca, M. (2002). Induction of MnSOD gene by arachidonic acid is mediated by reactive oxygen species and p38 MAPK signaling pathway in human HepG2 hepatoma cells. Free Radic. Biol. Med. 32, 1132–1142.

    Article  PubMed  CAS  Google Scholar 

  • Caballero, F., Fernandez, A., Matias, N., Martinez, L., Fucho, R., Elena, M., Caballeria, J., Morales, A., Fernandez-Checa, J.C., and Garcia-Ruiz, C. (2010). Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione. J. Biol. Chem. 285, 18528–18536.

    Article  PubMed  CAS  Google Scholar 

  • Chen, H.H., Chen, T.W., and Lin, H. (2010). Pravastatin attenuates carboplatin-induced nephrotoxicity in rodents via peroxisome proliferator-activated receptor alpha-regulated heme oxygenase-1. Mol. Pharmacol. 78, 36–45.

    Article  PubMed  CAS  Google Scholar 

  • Cheng, C.F., Lian, W.S., Chen, S.H., Lai, P.F., Li, H.F., Lan, Y.F., Cheng, W.T., and Lin, H. (2012). Protective effects of adiponectin against renal ischemia-reperfusion injury via prostacyclin-PPARalpha-heme oxygenase-1 signaling pathway. J. Cell Physiol. 227, 239–249.

    Article  PubMed  CAS  Google Scholar 

  • Dayal, S., Bottiglieri, T., Arning, E., Maeda, N., Malinow, M.R., Sigmund, C.D., Heistad, D.D., Faraci, F.M., and Lentz, S.R. (2001). Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine beta-synthase-deficient mice. Circ. Res. 88, 1203–1209.

    Article  PubMed  CAS  Google Scholar 

  • Erdmann, K., Cheung, B.W., Immenschuh, S., and Schroder, H. (2008). Heme oxygenase-1 is a novel target and antioxidant mediator of S-adenosylmethionine. Biochem. Biophys. Res. Commun. 368, 937–941.

    Article  PubMed  CAS  Google Scholar 

  • Esfandiari, F., You, M., Villanueva, J.A., Wong, D.H., French, S.W., and Halsted, C.H. (2007). S-adenosylmethionine attenuates hepatic lipid synthesis in micropigs fed ethanol with a folate-deficient diet. Alcohol Clin. Exp. Res. 31, 1231–1239.

    Article  PubMed  CAS  Google Scholar 

  • Han, S., Liang, C.P., DeVries-Seimon, T., Ranalletta, M., Welch, C.L., Collins-Fletcher, K., Accili, D., Tabas, I., and Tall, A.R. (2006). Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metab. 3, 257–266.

    Article  PubMed  CAS  Google Scholar 

  • Ji, C. (2012). Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries. Biochem. Res. Int. 2012, 216450.

    PubMed  Google Scholar 

  • Kaufman, R.J. (2002). Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 110, 1389–1398.

    PubMed  CAS  Google Scholar 

  • Kietzmann, T., Samoylenko, A., and Immenschuh, S. (2003). Transcriptional regulation of heme oxygenase-1 gene expression by MAP kinases of the JNK and p38 pathways in primary cultures of rat hepatocytes. J. Biol. Chem. 278, 17927–17936.

    Article  PubMed  CAS  Google Scholar 

  • Lee, K.U., Lee, I.K., Han, J., Song, D.K., Kim, Y.M., Song, H.S., Kim, H.S., Lee, W.J., Koh, E.H., Song, K.H., et al. (2005). Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis. Circ. Res. 96, 1200–1207.

    Article  PubMed  CAS  Google Scholar 

  • Leffler, C.W., Parfenova, H., and Jaggar, J.H. (2011). Carbon monoxide as an endogenous vascular modulator. Am. J. Physiol. Heart Circ. Physiol. 301, H1–H11.

    Article  PubMed  CAS  Google Scholar 

  • Lim, S., Moon, M.K., Shin, H., Kim, T.H., Cho, B.J., Kim, M., Park, H.S., Choi, S.H., Ko, S.H., Chung, M.H., et al. (2011). Effect of S-adenosylmethionine on neointimal formation after balloon injury in obese diabetic rats. Cardiovasc. Res. 90, 383–393.

    Article  PubMed  CAS  Google Scholar 

  • Mato, J.M., and Lu, S.C. (2007). Role of S-adenosyl-L-methionine in liver health and injury. Hepatology 45, 1306–1312.

    Article  PubMed  CAS  Google Scholar 

  • Miller, A.L. (2008). The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern. Med. Rev. 13, 216–226.

    PubMed  Google Scholar 

  • Ou, L., Wu, Y., Ip, C., Meng, X., Hsu, Y.C., and Ip, M.M. (2008). Apoptosis induced by t10,c12-conjugated linoleic acid is mediated by an atypical endoplasmic reticulum stress response. J. Lipid Res. 49, 985–994.

    Article  PubMed  CAS  Google Scholar 

  • Piantadosi, C.A., Carraway, M.S., Babiker, A., and Suliman, H.B. (2008). Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ. Res. 103, 1232–1240.

    Article  PubMed  CAS  Google Scholar 

  • Poschl, G., Stickel, F., Wang, X.D., and Seitz, H.K. (2004). Alcohol and cancer: genetic and nutritional aspects. Proc. Nutr. Soc. 63, 65–71.

    Article  PubMed  Google Scholar 

  • Rahman, I. (1999). Inflammation and the regulation of glutathione level in lung epithelial cells. Antioxid. Redox Signal. 1, 425–447.

    Article  PubMed  CAS  Google Scholar 

  • Rao, R.V., Ellerby, H.M., and Bredesen, D.E. (2004). Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ. 11, 372–380.

    Article  PubMed  CAS  Google Scholar 

  • Simopoulos, A.P. (2008). The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp. Biol. Med. (Maywood) 233, 674–688.

    Article  CAS  Google Scholar 

  • Soeken, K.L., Lee, W.L., Bausell, R.B., Agelli, M., and Berman, B.M. (2002). Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J. Fam. Pract. 51, 425–430.

    PubMed  Google Scholar 

  • Spijkerman, A.M., Smulders, Y.M., Kostense, P.J., Henry, R.M., Becker, A., Teerlink, T., Jakobs, C., Dekker, J.M., Nijpels, G., Heine R.J., et al. (2005). S-adenosylmethionine and 5-methyltetrahydrofolate are associated with endothelial function after controlling for confounding by homocysteine: the Hoorn Study. Arterioscler. Thromb. Vasc. Biol. 25, 778–784.

    Article  PubMed  CAS  Google Scholar 

  • Surh, Y.J., Kundu, J.K., Li, M.H., Na, H.K., and Cha, Y.N. (2009). Role of Nrf2-mediated heme oxygenase-1 upregulation in adaptive survival response to nitrosative stress. Arch. Pharm. Res. 32, 1163–1176.

    Article  PubMed  CAS  Google Scholar 

  • Szegezdi, E., Logue, S.E., Gorman, A.M., and Samali, A. (2006). Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7, 880–885.

    Article  PubMed  CAS  Google Scholar 

  • Tabas, I. (2010). The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ. Res. 107, 839–850.

    Article  PubMed  CAS  Google Scholar 

  • Tchantchou, F., Graves, M., Falcone, D., and Shea, T.B. (2008). Sadenosylmethionine mediates glutathione efficacy by increasing glutathione S-transferase activity: implications for S-adenosyl methionine as a neuroprotective dietary supplement. J. Alzheimers. Dis. 14, 323–328.

    PubMed  CAS  Google Scholar 

  • Vázquez-Chantada, M., Ariz, U., Varela-Rey, M., Embade, N., Martínez-Lopez, N., Fernández-Ramos, D., Gómez-Santos, L., Lamas, S., Lu, S.C., Martínez-Chantar, M.L., et al. (2009). Evidence for LKB1/AMP-activated protein kinase/endothelial nitric oxide synthase cascade regulated by hepatocyte growth factor, S-adenosylmethionine, and nitric oxide in hepatocyte proliferation. Hepatology 49, 608–617.

    Article  PubMed  Google Scholar 

  • Wagner, C., and Koury, M.J. (2007). S-Adenosylhomocysteine a better indicator of vascular disease than homocysteine? Am. J. Clin. Nutr. 86, 1581–1585.

    PubMed  CAS  Google Scholar 

  • Wang, C.Y., and Chau, L.Y. (2010). Heme oxygenase-1 in cardiovascular diseases: molecular mechanisms and clinical perspectives. Chang Gung Med. J. 33, 13–24.

    PubMed  CAS  Google Scholar 

  • Won, J.C., Park, J.Y., Kim, Y.M., Koh, E.H., Seol, S., Jeon, B.H., Han, J., Kim, J.R., Park, T.S., Choi, C.S., et al. (2010). Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha overexpression prevents endothelial apoptosis by increasing ATP/ADP translocase activity. Arterioscler. Thromb. Vasc. Biol. 30, 290–297.

    Article  PubMed  CAS  Google Scholar 

  • Wright, M.M., Kim, J., Hock, T.D., Leitinger, N., Freeman, B.A., and Agarwal, A. (2009). Human haem oxygenase-1 induction by nitrolinoleic acid is mediated by cAMP, AP-1 and E-box response element interactions. Biochem. J. 422, 353–361.

    Article  PubMed  CAS  Google Scholar 

  • Wu, D., and Cederbaum, A.I. (2006). Opposite action of S-adenosyl methionine and its metabolites on CYP2E1-mediated toxicity in pyrazole-induced rat hepatocytes and HepG2 E47 cells. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G674–G684.

    Article  PubMed  CAS  Google Scholar 

  • Wu, M.L., Ho, Y.C., and Yet, S.F. (2011). A central role of heme oxygenase-1 in cardiovascular protection. Antioxid. Redox Signal. 15, 1835–1846.

    Article  PubMed  CAS  Google Scholar 

  • Xu, H.E., Stanley, T.B., Montana, V.G., Lambert, M.H., Shearer, B.G., Cobb, J.E., McKee, D.D., Galardi, C.M., Plunket, K.D., Nolte, R.T., et al. (2002). Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature 14, 813–817.

    Article  Google Scholar 

  • Yu, J., Chu, E.S., Wang, R., Wang, S., Wu, C.W., Wong, V.W., Chan, H.L., Farrell, G.C., and Sung, J.J. (2010). Heme oxygenase-1 protects against steatohepatitis in both cultured hepatocytes and mice. Gastroenterology 138, 694–704.

    Article  PubMed  CAS  Google Scholar 

  • Yun, K.U., Ryu, C.S., Oh, J.M., Kim, C.H., Lee, K.S., Lee, C.H., Lee, H.S., Kim, B.H., and Kim, S.K. (2013). Plasma homocysteine level and hepatic sulfur amino acid metabolism in mice fed a high-fat diet. Eur. J. Nutr. 52, 127–134.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, 138-736, Korea

    Jung Eun Jang, Jaechan Leem, Ki-Up Lee & Eun Hee Koh

  2. Asan Institute for Life Sciences, Asan Medical Center, Seoul, 138-736, Korea

    Sun Young Kim, Mi-Ok Kim & Hyun-Sik Kim

  3. Department of Anatomy, College of Medicine, Inha University, Incheon, 401-103, Korea

    Seok Woo Hong & In-Sun Park

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  1. Sun Young Kim
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Correspondence to Eun Hee Koh.

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These authors contributed equally to this work.

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Kim, S.Y., Hong, S.W., Kim, MO. et al. S-adenosyl methionine prevents endothelial dysfunction by inducing heme oxygenase-1 in vascular endothelial cells. Mol Cells 36, 376–384 (2013). https://doi.org/10.1007/s10059-013-0210-y

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  • DOI: https://doi.org/10.1007/s10059-013-0210-y

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