Overexpression of Human Catalase Inhibits Proliferation and Promotes Apoptosis in Vascular Smooth Muscle Cells

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Abstract
—The role of reactive oxygen species, such as superoxide anions (O 2 · − ) and hydrogen peroxide (H 2 O 2 ), in modulating vascular smooth muscle cell proliferation and viability is controversial. To investigate the role of endogenously produced H 2 O 2 , rat aortic smooth muscle cells were infected with adenoviral vectors containing cDNA for human catalase (Ad Cat ) or a control gene, β-galactosidase (Ad LacZ ). Infection with Ad Cat resulted in dose-dependent increases in intracellular catalase protein, which was predominantly localized to peroxisomes. After infection with 100 multiplicity of infection (MOI) of Ad Cat , cellular catalase activity was increased by 50- to 100-fold, and intracellular H 2 O 2 concentration was reduced, as compared with control. Infection with Ad Cat reduced [ 3 H]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 [Ad LacZ ] versus 0.22±0.08 disintegrations per minute per cell [Ad Cat ], P Cat , cell numbers were reduced as compared with noninfected or Ad LacZ -infected cells (157 780±8413 [Ad Cat ], P LacZ ]). Furthermore, the number of apoptotic cells was increased 5-fold after infection with 100 MOI of Ad Cat as compared with control. Infection with Ad Cat resulted in induction of cyclooxygenase (COX)–2, and treatment with a COX-2 inhibitor overcame the Ad Cat -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 H 2 O 2 importantly modulates survival and proliferation of vascular smooth muscle cells.