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

Abstract

Reactive oxygen species such as hydrogen peroxide (H(2)O(2)) can positively and negatively modulate vascular smooth muscle cell (VSMC) growth. To investigate these paradoxical effects of H(2)O(2), we examined its effect on apoptosis, cell cycle progression, and cell cycle proteins. High concentrations of H(2)O(2) (500 microM to 1 mM) induced apoptosis, whereas moderate concentrations (100 microM) caused cell cycle arrest in G1. H(2)O(2) (100 microM) 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 H(2)O(2), whereas cyclin D1 mRNA was not affected. In addition, H(2)O(2) 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, H(2)O(2 )transiently increased p53 protein levels (3.16 +/- 1.2-fold at 2 h). Thus, whereas high levels of H(2)O(2) induce apoptosis, moderate concentrations of H(2)O(2) 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 H(2)O(2) in vascular disease.

NADPH Oxidase-Derived Overproduction of Reactive Oxygen Species Impairs Postischemic Neovascularization in Mice with Type 1 Diabetes

“…Conversely, higher amounts of ROS can bear negatively on vessel growth. 7,8,28,29 Nevertheless, because gp91…”

Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Injury

“…In general, apoptosis has been associated with higher levels of ROS than those that support proliferation (see below) (Deshpande et al 2002), such as those produced by macrophages and mechanical injury. Release of cytokines such as TNF-α following sepsis, ischemia reperfusion or shock contributes to endothelial apoptosis.…”

“…Furthermore, the concentration of H 2 O 2 is critically important for its effects on cells. High concentrations have been shown to be apoptotic, moderate doses cause cell arrest in the G1 phase, and low doses support proliferation (Baas et al 1995,Deshpande et al 2002. Finally, the intracellular location of H 2 O 2 production is likely important, as ROS producing enzymes are found both in caveolae and focal adhesions (Hilenski et al 2004).…”

Meta-analysis of C242T polymorphism in CYBA genes: risk of acute coronary syndrome is lower in Asians but not in Caucasians

“…Subgroup analysis by ethnicity documented a significant decreased risk of ACS under allelic comparison, dominant model, and homozygote comparison in the Asian population, while no significant association was observed among Caucasians. ROS were involved in plaque rupture and platelet aggregation (Galis et al, 1995;Bennett, 1999;Deshpande et al, 2002;Griendling and Fitzgerald, 2003), suggesting the important role of ROS in the pathological process of ACS. NAD(P)H oxidase is the predominant cellular source of ROS in the context of atherosclerosis (Mueller et al, 2005), which can be activated by p22phox (Sumimoto et al, 1996).…”

“…Reactive oxygen species (ROS), including nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite, play an important role in vascular pathophysiology and platelet aggregation (Griendling and Fitzgerald, 2003), which are also involved in the pathological process of ACS by activating matrix metalloproteinases (MMPs) (Galis et al, 1995), increasing smooth muscle cells apoptosis and thus leading to a plaque rupture (Bennett, 1999;Deshpande et al, 2002). NAD(P)H oxidase is the predominant cellular source of ROS in the atherosclerotic lesions (Mueller et al, 2005), which can be activated by p22phox (Sumimoto et al, 1996).…”