This Article Full Text Full Text (PDF) All Versions of this Article: 91/8/689    most recent 01.RES.0000037982.55074.F6v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schulze, P. C. Articles by Lee, R. T. Search for Related Content PubMed PubMed Citation Articles by Schulze, P. C. Articles by Lee, R. T. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Related Collections Cell signalling/signal transduction Growth factors/cytokines Smooth muscle proliferation and differentiation Oxidant stress

(Circulation Research. 2002;91:689.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Vitamin D₃–Upregulated Protein-1 (VDUP-1) Regulates Redox-Dependent Vascular Smooth Muscle Cell Proliferation Through Interaction With Thioredoxin

P. Christian Schulze, Gilles W. De Keulenaer, Jun Yoshioka, Kimberly A. Kassik, Richard T. Lee

From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Richard T. Lee, MD, Partners Research Facility, 65 Landsdowne St, Room 279, Cambridge, MA 02139. E-mail rlee{at}rics.bwh.harvard.edu

Reactive oxygen species are important cellular signaling molecules, and thioredoxin (TRX) is a key regulator of cellular redox balance. We investigated the interaction of TRX with its endogenous inhibitor, vitamin D₃–upregulated protein (VDUP)-1, in human aortic smooth muscle cells (SMCs). Adenoviral gene transfer of TRX enhanced TRX enzyme activity 2.7±0.4-fold (P<0.05 versus cells infected with adenoviral vector expressing green fluorescent protein [AdGFP]) and resulted in a 3.8±0.5-fold increase of cellular DNA synthesis as detected by methyl-[³H]thymidine incorporation (P<0.001). Platelet-derived growth factor (PDGF) also increased TRX enzyme activity 2.5±3.3-fold (P<0.05 versus no stimulation) and DNA synthesis 6.5±0.3-fold (P<0.001 versus no stimulation) without significant changes in TRX expression. PDGF and H₂O₂ time-dependently suppressed VDUP-1 expression (13-fold and 30-fold reduction after 1 hour, respectively; P<0.001), and this was inhibited by the cell-permeable antioxidants N-acetylcysteine and 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron). Overexpression of VDUP-1 (AdVDUP-1) reduced TRX activity at baseline (-61±23% versus control cells, P<0.05) and abolished PDGF-induced TRX activity (-9±27% in AdVDUP-1–infected cells; P=NS versus control cells). In addition, overexpression of VDUP-1 blocked PDGF-induced DNA synthesis (1.3±0.4-fold increase in AdVDUP-1–infected cells versus 6.5±0.4-fold increase in AdGFP-infected cells, P<0.001). In conclusion, VDUP-1 has marked antiproliferative effects in SMCs through the suppression of TRX activity, suggesting that the regulation of VDUP-1 is a critical molecular switch in the transduction of pro-oxidant mitogenic signals. These data also demonstrate that activation of the reductase TRX plays a pivotal role in the redox-dependent proliferation of SMCs.

Key Words: oxidative stress • growth factors • smooth muscle cells

This article has been cited by other articles:

				T. E. Tipple, S. E. Welty, L. D. Nelin, J. M. Hansen, and L. K. Rogers Alterations of the Thioredoxin System by Hyperoxia: Implications for Alveolar Development Am. J. Respir. Cell Mol. Biol., November 1, 2009; 41(5): 612 - 619. [Abstract] [Full Text] [PDF]

				Y. Kawashiro, H. Fukata, K. Sato, H. Aburatani, H. Takigami, and C. Mori Polybrominated diphenyl ethers cause oxidative stress in human umbilical vein endothelial cells Human and Experimental Toxicology, November 1, 2009; 28(11): 703 - 713. [Abstract] [PDF]

				W. Qi, X. Chen, J. Holian, C. Y.R. Tan, D. J. Kelly, and C. A. Pollock Transcription Factors Kruppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-{gamma} Mediate High Glucose-Induced Thioredoxin-Interacting Protein Am. J. Pathol., November 1, 2009; 175(5): 1858 - 1867. [Abstract] [Full Text] [PDF]

				S. Xu, Y. He, M. Vokurkova, and R. M. Touyz Endothelial Cells Negatively Modulate Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells: Role of Thioredoxin Hypertension, August 1, 2009; 54(2): 427 - 433. [Abstract] [Full Text] [PDF]

				E. Masson, S. Koren, F. Razik, H. Goldberg, E. P. Kwan, L. Sheu, H. Y. Gaisano, and I. G. Fantus High {beta}-cell mass prevents streptozotocin-induced diabetes in thioredoxin-interacting protein-deficient mice Am J Physiol Endocrinol Metab, June 1, 2009; 296(6): E1251 - E1261. [Abstract] [Full Text] [PDF]

				S.-T. Pang, W.-C. Hsieh, C.-K. Chuang, C.-H. Chao, W.-H. Weng, and H.-H. Juang Thioredoxin-interacting protein: an oxidative stress-related gene is upregulated by glucose in human prostate carcinoma cells J. Mol. Endocrinol., March 1, 2009; 42(3): 205 - 214. [Abstract] [Full Text] [PDF]

				J. Chen, G. Saxena, I. N. Mungrue, A. J. Lusis, and A. Shalev Thioredoxin-Interacting Protein: A Critical Link Between Glucose Toxicity and {beta}-Cell Apoptosis Diabetes, April 1, 2008; 57(4): 938 - 944. [Abstract] [Full Text] [PDF]

				S. T. Y. Hui, A. M. Andres, A. K. Miller, N. J. Spann, D. W. Potter, N. M. Post, A. Z. Chen, S. Sachithanantham, D. Y. Jung, J. K. Kim, et al. Txnip balances metabolic and growth signaling via PTEN disulfide reduction PNAS, March 11, 2008; 105(10): 3921 - 3926. [Abstract] [Full Text] [PDF]

				W. A. Chutkow, P. Patwari, J. Yoshioka, and R. T. Lee Thioredoxin-interacting Protein (Txnip) Is a Critical Regulator of Hepatic Glucose Production J. Biol. Chem., January 25, 2008; 283(4): 2397 - 2406. [Abstract] [Full Text] [PDF]

				R. A. Davis Searching for Causality of Knocking Out Txnip: Is Txnip Missing in Action? Circ. Res., December 7, 2007; 101(12): 1216 - 1218. [Full Text] [PDF]

				J. Yoshioka, K. Imahashi, S. A. Gabel, W. A. Chutkow, A. A. Burds, J. Gannon, P. C. Schulze, C. MacGillivray, R. E. London, E. Murphy, et al. Targeted Deletion of Thioredoxin-Interacting Protein Regulates Cardiac Dysfunction in Response to Pressure Overload Circ. Res., December 7, 2007; 101(12): 1328 - 1338. [Abstract] [Full Text] [PDF]

				F. Turturro, G. Von Burton, and E. Friday Hyperglycemia-Induced Thioredoxin-Interacting Protein Expression Differs in Breast Cancer-Derived Cells and Regulates Paclitaxel IC50 Clin. Cancer Res., June 15, 2007; 13(12): 3724 - 3730. [Abstract] [Full Text] [PDF]

				M. Kobayashi-Miura, K. Shioji, Y. Hoshino, H. Masutani, H. Nakamura, and J. Yodoi Oxygen sensing and redox signaling: the role of thioredoxin in embryonic development and cardiac diseases Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2040 - H2050. [Abstract] [Full Text] [PDF]

				P. C. Schulze, H. Liu, E. Choe, J. Yoshioka, A. Shalev, K. D. Bloch, and R. T. Lee Nitric Oxide-Dependent Suppression of Thioredoxin-Interacting Protein Expression Enhances Thioredoxin Activity Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2666 - 2672. [Abstract] [Full Text] [PDF]

				P. Patwari, L. J. Higgins, W. A. Chutkow, J. Yoshioka, and R. T. Lee The Interaction of Thioredoxin with Txnip: EVIDENCE FOR FORMATION OF A MIXED DISULFIDE BY DISULFIDE EXCHANGE J. Biol. Chem., August 4, 2006; 281(31): 21884 - 21891. [Abstract] [Full Text] [PDF]

				R. E. Clempus and K. K. Griendling Reactive oxygen species signaling in vascular smooth muscle cells Cardiovasc Res, July 15, 2006; 71(2): 216 - 225. [Abstract] [Full Text] [PDF]

				G.-H. Liu, J. Qu, and X. Shen Thioredoxin-mediated Negative Autoregulation of Peroxisome Proliferator-activated Receptor {alpha} Transcriptional Activity Mol. Biol. Cell, April 1, 2006; 17(4): 1822 - 1833. [Abstract] [Full Text] [PDF]

				C. E. Filby, S. B. Hooper, F. Sozo, V. A. Zahra, S. J. Flecknoe, and M. J. Wallace VDUP1: a potential mediator of expansion-induced lung growth and epithelial cell differentiation in the ovine fetus Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L250 - L258. [Abstract] [Full Text] [PDF]

				G. Xiang, T. Seki, M. D. Schuster, P. Witkowski, A. J. Boyle, F. See, T. P. Martens, A. Kocher, H. Sondermeijer, H. Krum, et al. Catalytic Degradation of Vitamin D Up-regulated Protein 1 mRNA Enhances Cardiomyocyte Survival and Prevents Left Ventricular Remodeling after Myocardial Ischemia J. Biol. Chem., November 25, 2005; 280(47): 39394 - 39402. [Abstract] [Full Text] [PDF]

				A. H. Minn, C. Hafele, and A. Shalev Thioredoxin-Interacting Protein Is Stimulated by Glucose through a Carbohydrate Response Element and Induces {beta}-Cell Apoptosis Endocrinology, May 1, 2005; 146(5): 2397 - 2405. [Abstract] [Full Text] [PDF]

				B. J. Deroo, S. C. Hewitt, S. D. Peddada, and K. S. Korach Estradiol Regulates the Thioredoxin Antioxidant System in the Mouse Uterus Endocrinology, December 1, 2004; 145(12): 5485 - 5492. [Abstract] [Full Text] [PDF]

				C. J. Lowenstein Exogenous Thioredoxin Reduces Inflammation in Autoimmune Myocarditis Circulation, September 7, 2004; 110(10): 1178 - 1179. [Full Text] [PDF]

				Y. Nishinaka, H. Masutani, S.-i. Oka, Y. Matsuo, Y. Yamaguchi, K. Nishio, Y. Ishii, and J. Yodoi Importin {alpha}1 (Rch1) Mediates Nuclear Translocation of Thioredoxin-binding Protein-2/Vitamin D3-up-regulated Protein 1 J. Biol. Chem., September 3, 2004; 279(36): 37559 - 37565. [Abstract] [Full Text] [PDF]

				J. Haendeler, J. Hoffmann, A. M. Zeiher, and S. Dimmeler Antioxidant Effects of Statins via S-Nitrosylation and Activation of Thioredoxin in Endothelial Cells: A Novel Vasculoprotective Function of Statins Circulation, August 17, 2004; 110(7): 856 - 861. [Abstract] [Full Text] [PDF]

				S. E Hardt and J. Sadoshima Negative regulators of cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 500 - 509. [Abstract] [Full Text] [PDF]

				P. C. Schulze, J. Yoshioka, T. Takahashi, Z. He, G. L. King, and R. T. Lee Hyperglycemia Promotes Oxidative Stress through Inhibition of Thioredoxin Function by Thioredoxin-interacting Protein J. Biol. Chem., July 16, 2004; 279(29): 30369 - 30374. [Abstract] [Full Text] [PDF]

				J. Yoshioka, P. C. Schulze, M. Cupesi, J. D. Sylvan, C. MacGillivray, J. Gannon, H. Huang, and R. T. Lee Thioredoxin-Interacting Protein Controls Cardiac Hypertrophy Through Regulation of Thioredoxin Activity Circulation, June 1, 2004; 109(21): 2581 - 2586. [Abstract] [Full Text] [PDF]

				D. G Simmons and T. G Kennedy Rat endometrial Vdup1 expression: changes related to sensitization for the decidual cell reaction and hormonal control Reproduction, April 1, 2004; 127(4): 475 - 482. [Abstract] [Full Text] [PDF]

				A. G. Passerini, D. C. Polacek, C. Shi, N. M. Francesco, E. Manduchi, G. R. Grant, W. F. Pritchard, S. Powell, G. Y. Chang, C. J. Stoeckert Jr., et al. Coexisting proinflammatory and antioxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta PNAS, February 24, 2004; 101(8): 2482 - 2487. [Abstract] [Full Text] [PDF]

				H. Yamawaki, J. Haendeler, and B. C. Berk Thioredoxin: A Key Regulator of Cardiovascular Homeostasis Circ. Res., November 28, 2003; 93(11): 1029 - 1033. [Abstract] [Full Text] [PDF]

				S. Hassan, B. Duong, K.-S. Kim, and M. F. Miles Pharmacogenomic Analysis of Mechanisms Mediating Ethanol Regulation of Dopamine {beta}-Hydroxylase J. Biol. Chem., October 3, 2003; 278(40): 38860 - 38869. [Abstract] [Full Text] [PDF]