Mechanism of Hydrogen Peroxide-Induced Cell Cycle Arrest in Vascular Smooth Muscle

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Abstract
Reactive oxygen species such as hydrogen peroxide (H2O2) can positively and negatively modulate vascular smooth muscle cell (VSMC) growth. To investigate these paradoxical effects of H2O2, we examined its effect on apoptosis, cell cycle progression, and cell cycle proteins. High concentrations of H2O2 (500 µM to 1 mM) induced apoptosis, whereas moderate concentrations (100 µM) caused cell cycle arrest in G1. H2O2 (100 µM) blocked serum-stimulated cyclin-dependent kinase-2 (CDK2) activity, but not CDK4 activity, suggesting that cell cycle arrest occurred in part by inhibiting CDK2 activity. The serum-induced increase in cyclin A mRNA was also completely suppressed by H2O2, whereas cyclin D1 mRNA was not affected. In addition, H2O2 caused a dramatic increase in expression of the cell cycle inhibitor p21 mRNA (9.67 ± 0.94-fold at 2 h) and protein (8.75 ± 0.08-fold at 8 h), but no change in p27 protein. Finally, H2O2 transiently increased p53 protein levels (3.16 ± 1.2-fold at 2 h). Thus, whereas high levels of H2O2 induce apoptosis, moderate concentrations of H2O2 coordinate a set of molecular events leading to arrest of VSMCs at the G1/S checkpoint of the cell cycle. These results provide insight into the mechanisms underlying positive and negative regulation of VSMC growth by H2O2 in vascular disease.