© 1999 American Heart Association, Inc.
Cellular Biology |
Overexpression of Human Catalase Inhibits Proliferation and Promotes Apoptosis in Vascular Smooth Muscle Cells
From the Departments of Surgery (M.R.B.), Internal Medicine (F.J.M., W.-G.L., J.D.M., P.C., A.A.S., N.L.W.), Anatomy and Cell Biology (J.F.E.), and Biochemistry (A.N.E., X.F., A.A.S.), and Radiation Research Laboratory (L.W.O.), University of Iowa College of Medicine, Iowa City, Iowa; Institute for Human Gene Therapy (R.M.Z.), University of Pennsylvania Medical Center, Philadelphia, Pa; and Department of Surgery (R.M.Z.), University of Edinburgh, MRC Human Genetics Unit, Edinburgh, UK.
Correspondence to Dr Neal L. Weintraub, Department of Internal Medicine, Cardiovascular Division, E-329GH, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail neal-weintraub{at}uiowa.edu
Abstract—The role of reactive oxygen species, such as superoxide anions (O2·-) and hydrogen peroxide (H2O2), in modulating vascular smooth muscle cell proliferation and viability is controversial. To investigate the role of endogenously produced H2O2, rat aortic smooth muscle cells were infected with adenoviral vectors containing cDNA for human catalase (AdCat) or a control gene, ß-galactosidase (AdLacZ). Infection with AdCat resulted in dose-dependent increases in intracellular catalase protein, which was predominantly localized to peroxisomes. After infection with 100 multiplicity of infection (MOI) of AdCat, cellular catalase activity was increased by 50- to 100-fold, and intracellular H2O2 concentration was reduced, as compared with control. Infection with AdCat reduced [3H]thymidine uptake, an index of DNA synthesis, in cells maintained in medium supplemented with 2% serum (0.37±0.09 disintegrations per minute per cell [AdLacZ] versus 0.22±0.08 disintegrations per minute per cell [AdCat], P<0.05). Five days after infection with 100 MOI of AdCat, cell numbers were reduced as compared with noninfected or AdLacZ-infected cells (157 780±8413 [AdCat], P<0.05 versus 233 700±3032 [noninfected] or 222 410±5332 [AdLacZ]). Furthermore, the number of apoptotic cells was increased 5-fold after infection with 100 MOI of AdCat as compared with control. Infection with AdCat resulted in induction of cyclooxygenase (COX)–2, and treatment with a COX-2 inhibitor overcame the AdCat-induced reduction in cell numbers. These findings indicate that overexpression of catalase inhibited smooth muscle proliferation while increasing the rate of apoptosis, possibly through a COX-2–dependent mechanism. Our results suggest that endogenously produced H2O2 importantly modulates survival and proliferation of vascular smooth muscle cells.
Key Words: catalase • apoptosis • vascular smooth muscle cell • cell proliferation • hydrogen peroxide
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