| 19341793 |
Onumah OE, Jules GE, Zhao Y, Zhou L, Yang H, Guo Z: Overexpression of catalase delays G0/G1- to S-phase transition during cell cycle progression in mouse aortic endothelial cells. Free Radic Biol Med. 2009 Jun 15;46(12):1658-67. Epub 2009 Mar 31.
Although it is understood that hydrogen peroxide (H (2) O (2)) promotes cellular proliferation, little is known about its role in endothelial cell cycle progression. To assess the regulatory role of endogenously produced H (2) O (2) in cell cycle progression, we studied the cell cycle progression in mouse aortic endothelial cells (MAECs) obtained from mice overexpressing a human catalase transgene (hCatTg), which destroys H (2) O (2). The hCatTg MAECs displayed a prolonged doubling time compared to wild-type controls (44.0 +/- 4.7 h versus 28.6 +/- 0.8 h, p <0.05), consistent with a diminished growth rate and H (2) O (2) release. Incubation with aminotriazole, a catalase inhibitor, prevented the observed diminished growth rate in hCatTg MAECs. Inhibition of catalase activity with aminotriazole abrogated catalase overexpression-induced antiproliferative action. Flow cytometry analysis indicated that the prolonged doubling time was principally due to an extended G (0)/G (1) phase in hCatTg MAECs compared to the wild-type cells (25.0 +/- 0.9 h versus 15.9 +/- 1.4 h, p < 0.05). The hCatTg MAECs also exhibited decreased activities of the cyclin-dependent kinase (Cdk) complexes responsible for G (0)/G (1)- to S-phase transition in the cell cycle, including the cyclin D-Cdk4 and cyclin E-Cdk2 complexes. Moreover, the reduction in cyclin-Cdk activities in hCatTg MAECs was accompanied by increased protein levels of two Cdk inhibitors, p21 and p27, which inhibit the Cdk activity required for the G (0)/G (1)- to S-phase transition. Knockdown of p21 and/or p27 attenuated the antiproliferative effect of catalase overexpression in MAECs. These results, together with the fact that catalase is an H (2) O (2) scavenger, suggest that endogenously produced H (2) O (2) mediates MAEC proliferation by fostering the transition from G (0)/G (1) to S phase. |
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