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KMID : 0354720060300060416
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Journal of Korean Diabetes Association
2006 Volume.30 No. 6 p.416 ~ p.427
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High Glucose Modulates Vascular Smooth Muscle Cell Proliferation Through Activation of PKC-δ-dependent NAD(P)H oxidase
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Kim Bo-Hyun
Lee Chang-Won
Park Jung-Lae
Kang Yang-Ho
Kim In-Ju
Kim Yong-Gi
Son Suk-Man
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Abstract
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Background:Oxidative stress is thought to be one of the causative factors contributing to macrovascular omplications in diabetes. However, the mechanisms of development and progression of diabetic vascular complications are poorly understood. We hypothesized that PKC-δ isozyme contributes to ROS generation and determined their roles in the critical intermediary signaling events in high glucose-induced proliferation of vascular smooth muscle (VSM) cells.
Methods:We treated primary cultured rat aortic smooth muscle cells for 72 hours with medium containing 5.5 mmol/L D-glucose (normal glucose), 30 mmol/L D-glucose (high glucose) or 5.5 mmol/L D-glucose plus 24.5 mmol/L mannitol (osmotic control). We then measured cell number, BrdU incorporation, cell cycle and superoxide production in VSM cells. Immunoblotting of PKC isozymes using phoshospecific antibodies was performed, and PKC activity was also measured.
Results:High glucose increased VSM cell number and BrdU incorporation and displayed significantly greater percentages of S and G2/M phases than compared to 5.5 mmol/L glucose and osmotic control. The nitroblue tetrazolium (NBT) staining in high glucose-treated VSM cell was more prominent compared with normal glucose-treated VSM cell, which was significantly inhibited by DPI (10 μM), but not by inhibitors for other oxidases. High glucose also markedly increased activity of PKC-δ isozyme. When VSM cells were treated with rottlerin, a specific inhibitor of PKC-δ or transfected with PKC-δ siRNA, NBT staining and NAD(P)H oxidase activity were significantly attenuated in the high glucose-treated VSM cells.Furthermore, inhibition of PKC-δ markedly decreased VSM cell number by high glucose.
Conclusion:These results suggest that high glucose-induced VSM cell proliferation is dependent upon activation of PKC-δ, which may responsible for elevated intracellular ROS production in VSM cells, and this is mediated by NAD(P)H xidase.
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KEYWORD
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Diabetic vascular complication, High glucose, NAD(P)H oxidase, PKC-δ, Vascular smooth muscle cell
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