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(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

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