{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T12:53:57Z","timestamp":1762520037389},"reference-count":38,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2007,12]]},"abstract":"<jats:p> Although elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with increased inflammation and vascular remodeling, the mechanism of Hcy-mediated inflammation and vascular remodeling is unclear. The matrix metalloproteinases (MMPs) and adhesion molecules play an important role in vascular remodeling. We hypothesized that HHcy induces inflammation by increasing adhesion molecules and matrix protein expression. Endothelial cells were supplemented with high methionine, and Hcy accumulation was measured by HPLC. Nitric oxide (NO) bioavailability was detected by a NO probe. The protein expression was measured by Western blot analysis. MMP-9 activity was detected by gelatin-gel zymography. We demonstrated that methionine supplement promoted upregulation of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) through increased Hcy accumulation. In addition, increased synthesis of collagen type-1 was also observed. MMP-9 gene expression and protein activity were increased in methionine supplement groups. 3-Deazaadenosine (DZA), an adenosine analogue, prevented high methionine-induced ICAM-1 and VCAM-1 expression and collagen type-1 synthesis. Transfection of endothelial cells with cystathionine-\u03b2-synthase (CBS) gene construct, which converts Hcy to cystathionine, reduced Hcy accumulation in high methionine-fed cells. CBS gene transfection reduced the inflammatory response, as evident by attenuated ICAM-1 and VCAM-1 expression. Furthermore, collagen type-1 expression and MMP-9 activity were dramatically attenuated with CBS gene transfection. These results suggested that methionine supplement increased Hcy accumulation, which was associated with inflammatory response and matrix remodeling such as collagen type-1 synthesis and MMP-9 activity. However, in vitro DZA and CBS gene therapy successfully treated the HHcy-induced inflammatory reaction in the methionine metabolism pathway. <\/jats:p>","DOI":"10.1152\/ajpcell.00207.2007","type":"journal-article","created":{"date-parts":[[2007,9,14]],"date-time":"2007-09-14T01:39:02Z","timestamp":1189733942000},"page":"C1779-C1787","source":"Crossref","is-referenced-by-count":30,"title":["Cystathionine-\u03b2-synthase gene transfer and 3-deazaadenosine ameliorate inflammatory response in endothelial cells"],"prefix":"10.1152","volume":"293","author":[{"given":"Utpal","family":"Sen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neetu","family":"Tyagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Munish","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karni S.","family":"Moshal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter E.","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh C.","family":"Tyagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"crossref","unstructured":"Aksamit RR, Falk W, Cantoni GL. Inhibition of chemotaxis by S-3-deazaadenosylhomocysteine in a mouse macrophage cell line. J Biol Chem 257: 621\u2013625, 1982.","DOI":"10.1016\/S0021-9258(19)68238-4"},{"key":"R2","doi-asserted-by":"crossref","unstructured":"Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87: 840\u2013844, 2000.","DOI":"10.1161\/01.RES.87.10.840"},{"key":"R3","doi-asserted-by":"crossref","unstructured":"Dayal S, Bottiglieri T, Arning E, Maeda N, Malinow MR, Sigmund CD, Heistad DD, Faraci FM, Lentz SR. Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine beta-synthase-deficient mice. Circ Res 88: 1203\u20131209, 2001.","DOI":"10.1161\/hh1101.092180"},{"key":"R4","doi-asserted-by":"crossref","unstructured":"Dayal S, Wilson KM, Leo L, Arning E, Bottiglieri T, Lentz SR. Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia. Blood 108: 2237\u20132243, 2006.","DOI":"10.1182\/blood-2006-02-005991"},{"key":"R5","doi-asserted-by":"crossref","unstructured":"Dudman NP, Temple SE, Guo XW, Fu W, Perry MA. Homocysteine enhances neutrophil-endothelial interactions in both cultured human cells and rats in vivo. Circ Res 84: 409\u2013416, 1999.","DOI":"10.1161\/01.RES.84.4.409"},{"key":"R6","doi-asserted-by":"crossref","unstructured":"Faggiotto A, Ross R. Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque. Arteriosclerosis 4: 341\u2013356, 1984.","DOI":"10.1161\/01.ATV.4.4.341"},{"key":"R7","unstructured":"Giusti B, Marcucci R, Lapini I, Sestini I, Lenti M, Yacoub M, Pepe G. Role of hyperhomocysteinemia in aortic disease. Cell Mol Biol (Noisy-le-grand) 50: 945\u2013452, 2004."},{"key":"R8","doi-asserted-by":"crossref","unstructured":"Goode GK, Heagerty AM. In vitro responses of human peripheral small arteries in hypercholesterolemia and effects of therapy. Circulation 91: 2898\u20132903, 1995.","DOI":"10.1161\/01.CIR.91.12.2898"},{"key":"R9","doi-asserted-by":"crossref","unstructured":"Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation 108: 2034\u20132040, 2003.","DOI":"10.1161\/01.CIR.0000093661.90582.c4"},{"key":"R10","doi-asserted-by":"crossref","unstructured":"Henricson J, Tesselaar E, Persson K, Nilsson G, Sjoberg F. Assessment of microvascular function by study of the dose-response effects of iontophoretically applied drugs (acetylcholine and sodium nitroprusside)\u2013methods and comparison with in vitro studies. Microvasc Res 73: 143\u2013149, 2007.","DOI":"10.1016\/j.mvr.2006.10.004"},{"key":"R11","doi-asserted-by":"crossref","unstructured":"Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf BM, Tanji N, Ferran LJ Jr, Kohl B, Rao V, Kisiel W, Stern DM, Schmidt AM. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 107: 675\u2013683, 2001.","DOI":"10.1172\/JCI10588"},{"key":"R12","doi-asserted-by":"crossref","unstructured":"Jacobsen DW. Hyperhomocysteinemia and oxidative stress: time for a reality check? Arterioscler Thromb Vasc Biol 20: 1182\u20131184, 2000.","DOI":"10.1161\/01.ATV.20.5.1182"},{"key":"R13","doi-asserted-by":"crossref","unstructured":"Jeong SY, Ahn SG, Lee JH, Kim HS, Kim JW, Rhim H, Jeong SW, Kim IK. 3-deazaadenosine, a S-adenosylhomocysteine hydrolase inhibitor, has dual effects on NF-kappaB regulation. Inhibition of NF-kappaB transcriptional activity and promotion of IkappaBalpha degradation. J Biol Chem 274: 18981\u201318988, 1999.","DOI":"10.1074\/jbc.274.27.18981"},{"key":"R14","doi-asserted-by":"crossref","unstructured":"Johnson C, Galis ZS. Matrix metalloproteinase-2 and -9 differentially regulate smooth muscle cell migration and cell-mediated collagen organization. Arterioscler Thromb Vasc Biol 24: 54\u201360, 2004.","DOI":"10.1161\/01.ATV.0000100402.69997.C3"},{"key":"R15","doi-asserted-by":"crossref","unstructured":"Jurgensen CH, Huber BE, Zimmerman TP, Wolberg G. 3-deazaadenosine inhibits leukocyte adhesion and ICAM-1 biosynthesis in tumor necrosis factor-stimulated human endothelial cells. J Immunol 144: 653\u2013661, 1990.","DOI":"10.4049\/jimmunol.144.2.653"},{"key":"R16","doi-asserted-by":"crossref","unstructured":"Langheinrich AC, Braun-Dullaeus RC, Walker G, Jeide I, Schilling R, Tammoscheit K, Dreyer T, Fink L, Bohle RM, Haberbosch W. Effects of 3-deazaadenosine on homocysteine and atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 171: 181\u2013192, 2003.","DOI":"10.1016\/j.atherosclerosis.2003.08.028"},{"key":"R17","doi-asserted-by":"crossref","unstructured":"Lee KS, Jin SM, Kim HJ, Lee YC. Matrix metalloproteinase inhibitor regulates inflammatory cell migration by reducing ICAM-1 and VCAM-1 expression in a murine model of toluene diisocyanate-induced asthma. J Allergy Clin Immunol 111: 1278\u20131284, 2003.","DOI":"10.1067\/mai.2003.1501"},{"key":"R18","doi-asserted-by":"crossref","unstructured":"Malinow MR, Kang SS, Taylor LM, Wong PW, Coull B, Inahara T, Mukerjee D, Sexton G, Upson B. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 79: 1180\u20131188, 1989.","DOI":"10.1161\/01.CIR.79.6.1180"},{"key":"R19","doi-asserted-by":"crossref","unstructured":"Moshal KS, Sen U, Tyagi N, Henderson B, Steed M, Ovechkin AV, Tyagi SC. Regulation of homocysteine-induced MMP-9 by ERK1\/2 pathway. Am J Physiol Cell Physiol 290: C883\u2013C891, 2006.","DOI":"10.1152\/ajpcell.00359.2005"},{"key":"R20","doi-asserted-by":"crossref","unstructured":"Murata K, Motayama T, Kotake C. Collagen types in various layers of the human aorta and their changes with the atherosclerotic process. Atherosclerosis 60: 251\u2013262, 1986.","DOI":"10.1016\/0021-9150(86)90172-3"},{"key":"R21","doi-asserted-by":"crossref","unstructured":"Nagase H, Woessner JF, Jr. Matrix metalloproteinases. J Biol Chem 274: 21491\u201321494, 1999.","DOI":"10.1074\/jbc.274.31.21491"},{"key":"R22","doi-asserted-by":"crossref","unstructured":"Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 18: 842\u2013851, 1998.","DOI":"10.1161\/01.ATV.18.5.842"},{"key":"R23","doi-asserted-by":"crossref","unstructured":"Ovechkin AV, Tyagi N, Sen U, Lominadze D, Steed MM, Moshal KS, Tyagi SC. 3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice. Am J Physiol Lung Cell Mol Physiol 291: L905\u2013L911, 2006.","DOI":"10.1152\/ajplung.00543.2005"},{"key":"R24","doi-asserted-by":"crossref","unstructured":"Postea O, Krotz F, Henger A, Keller C, Weiss N. Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine. Arterioscler Thromb Vasc Biol 26: 508\u2013513, 2006.","DOI":"10.1161\/01.ATV.0000201039.21705.dc"},{"key":"R25","doi-asserted-by":"crossref","unstructured":"Prudova A, Bauman Z, Braun A, Vitvitsky V, Lu SC, Banerjee R. S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity. Proc Natl Acad Sci USA 103: 6489\u20136494, 2006.","DOI":"10.1073\/pnas.0509531103"},{"key":"R26","doi-asserted-by":"crossref","unstructured":"Rekhter MD. Collagen synthesis in atherosclerosis: too much and not enough. Cardiovasc Res 41: 376\u2013384, 1999.","DOI":"10.1016\/S0008-6363(98)00321-6"},{"key":"R27","doi-asserted-by":"crossref","unstructured":"Ross R. Atherosclerosis\u2013an inflammatory disease. N Engl J Med 340: 115\u2013126, 1999.","DOI":"10.1056\/NEJM199901143400207"},{"key":"R28","doi-asserted-by":"crossref","unstructured":"Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101: 1899\u20131906, 2000.","DOI":"10.1161\/01.CIR.101.16.1899"},{"key":"R29","doi-asserted-by":"crossref","unstructured":"Sen U, Moshal KS, Tyagi N, Kartha GK, Tyagi SC. Homocysteine-induced myofibroblast differentiation in mouse aortic endothelial cells. J Cell Physiol 209: 767\u2013774, 2006.","DOI":"10.1002\/jcp.20752"},{"key":"R30","doi-asserted-by":"crossref","unstructured":"Silverman MD, Tumuluri RJ, Davis M, Lopez G, Rosenbaum JT, Lelkes PI. Homocysteine upregulates vascular cell adhesion molecule-1 expression in cultured human aortic endothelial cells and enhances monocyte adhesion. Arterioscler Thromb Vasc Biol 22: 587\u2013592, 2002.","DOI":"10.1161\/01.ATV.0000014221.30108.08"},{"key":"R31","doi-asserted-by":"crossref","unstructured":"Srivastava S, D'Souza SE, Sen U, States JC. In utero arsenic exposure induces early onset of atherosclerosis in ApoE\u2212\/\u2212 mice. Reprod Toxicol 23: 449\u2013456, 2007.","DOI":"10.1016\/j.reprotox.2007.01.005"},{"key":"R32","doi-asserted-by":"crossref","unstructured":"Stamler JS, Osborne JA, Jaraki O, Rabbani LE, Mullins M, Singel D, Loscalzo J. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 91: 308\u2013318, 1993.","DOI":"10.1172\/JCI116187"},{"key":"R33","unstructured":"Taub JW, Huang X, Ge Y, Dutcher JA, Stout ML, Mohammad RM, Ravindranath Y, Matherly LH. Cystathionine-beta-synthase cDNA transfection alters the sensitivity and metabolism of 1-beta-d-arabinofuranosylcytosine in CCRF-CEM leukemia cells in vitro and in vivo: a model of leukemia in Down syndrome. Cancer Res 60: 6421\u20136426, 2000."},{"key":"R34","doi-asserted-by":"crossref","unstructured":"Tyagi SC, Kumar SG, Haas SJ, Reddy HK, Voelker DJ, Hayden MR, Demmy TL, Schmaltz RA, Curtis JJ. Post-transcriptional regulation of extracellular matrix metalloproteinase in human heart end-stage failure secondary to ischemic cardiomyopathy. J Mol Cell Cardiol 28: 1415\u20131428, 1996.","DOI":"10.1006\/jmcc.1996.0132"},{"key":"R35","doi-asserted-by":"crossref","unstructured":"Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 272: 17012\u201317017, 1997.","DOI":"10.1074\/jbc.272.27.17012"},{"key":"R36","doi-asserted-by":"crossref","unstructured":"Walker G, Langheinrich AC, Dennhauser E, Bohle RM, Dreyer T, Kreuzer J, Tillmanns H, Braun-Dullaeus RC, Haberbosch W. 3-deazaadenosine prevents adhesion molecule expression and atherosclerotic lesion formation in the aortas of C57BL\/6J mice. Arterioscler Thromb Vasc Biol 19: 2673\u20132679, 1999.","DOI":"10.1161\/01.ATV.19.11.2673"},{"key":"R37","doi-asserted-by":"crossref","unstructured":"Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 338: 1042\u20131050, 1998.","DOI":"10.1056\/NEJM199804093381507"},{"key":"R38","doi-asserted-by":"crossref","unstructured":"Whatling C, McPheat W, Hurt-Camejo E. Matrix management: assigning different roles for MMP-2 and MMP-9 in vascular remodeling. Arterioscler Thromb Vasc Biol 24: 10\u201311, 2004.","DOI":"10.1161\/01.ATV.0000100562.63144.C1"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00207.2007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T17:40:51Z","timestamp":1718646051000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00207.2007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,12]]},"references-count":38,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2007,12]]}},"alternative-id":["10.1152\/ajpcell.00207.2007"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00207.2007","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"value":"0363-6143","type":"print"},{"value":"1522-1563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,12]]}}}