Circulation Research. 2003
Published online before print August 21, 2003, doi: 10.1161/01.RES.0000091828.36599.34
Published online before print August 21, 2003, doi: 10.1161/01.RES.0000091828.36599.34
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Submitted on March 18, 2003
Revised on August 8, 2003
Accepted on August 8, 2003
Heme Oxygenase-1 Attenuates Glucose-Mediated Cell Growth Arrest and Apoptosis in Human Microvessel Endothelial Cells
Nader G. Abraham *;
From the Departments of Pharmacology (N.G.A., T.K., S.Q.) and Physiology (M.W.), Cardiology Division and Department of Medicine (J.M., R.L., Z.D.), New York Medical College, Valhalla, NY, and Rockefeller University (N.G.A.), New York, NY.
* To whom correspondence should be addressed. E-mail: nader_abraham{at}nymc.edu.
Heme oxygenase-1 (HO-1) is a stress protein that has been suggested to participate in defense mechanisms against agents that may induce oxidative injury, such as heme and inflammatory molecules. Incubation of endothelial cells in a high-glucose (33 mmol/L) medium for 7 days resulted in a decrease of HO activity by 34% and a decrease in HO-1 and HO-2 proteins compared with cells exposed to low glucose (5 mmol/L) (P<0.05) or cells exposed to mannitol (33 mmol/L). Overexpression of HO-1 was coupled with an increase in HO activity and carbon monoxide synthesis, decreased cellular heme, and acceleration in all phases of the cell cycle (P<0.001). The rate of cell cycle or cell birth rate was increased by 29% (P<0.05) in cells overexpressing HO-1 but decreased by 23% (P<0.05) in cells underexpressing HO-1 compared with control cells. Exposure to high glucose significantly decreased cell-cycle progression in control cells and in cells underexpressing HO-1 but did not decrease cell-cycle progression in cells overexpressing HO-1. High glucose induced p21 and p27 in control cells but not in cells overexpressing HO-1. The addition of tin-mesoporphyrin (SnMP), an inhibitor of HO activity, reversed the HO-1-mediated decrease of p21 and p27 in cells overexpressing HO-1. These findings identify a novel effect of HO-1 on endothelial cell growth and indicate that heme metabolism and HO-1 expression regulate signaling systems in cells exposed to high glucose, which controls cell-cycle progression.
Key words: cell cycle • oxidative stress • superoxide anion production • gene transfer • heme oxygenase
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