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Diabetic LDL inhibits cell-cycle progression via STAT5B and p21waf
Maria Felice Brizzi, … , Gianfranco Pagano, Luigi Pegoraro
Maria Felice Brizzi, … , Gianfranco Pagano, Luigi Pegoraro
Published January 1, 2002
Citation Information: J Clin Invest. 2002;109(1):111-119. https://doi.org/10.1172/JCI13617.
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Diabetic LDL inhibits cell-cycle progression via STAT5B and p21waf

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Abstract

Modified LDL is a major cause of injury to the endothelium in diabetes. In the present study, we analyzed the effects on endothelial cells of LDL recovered from type 2 diabetic patients (dm-LDL) or from nondiabetic subjects (n-LDL). Treatment of human umbilical vein endothelial cells with dm-LDL, but not n-LDL, led to the accumulation of cells in G1. To dissect the molecular mechanisms of this effect, we analyzed the expression and function of the cyclin-dependent kinase inhibitor p21waf, a cell cycle regulator known to be a target of the signal transducers and activators of transcription (STATs). dm-LDL led to transient STAT5 phosphorylation and the formation of a STAT5-containing complex and activated p21waf expression at the transcriptional level. Expression of the dominant-negative form of STAT5B, but not of STAT5A, significantly decreased both p21waf expression and the fraction of cells in G1. Finally, immunofluorescence analysis demonstrated that activated STAT5 is expressed in newly formed intraplaque vessels and in endothelial cells lining the luminal side of the plaque. Similarly, p21waf immunoreactivity was found in the neointimal vasculature. Our results suggest a role of STAT5B as a regulator of gene expression in diabetes-associated vascular disease.

Authors

Maria Felice Brizzi, Patrizia Dentelli, Marzia Pavan, Arturo Rosso, Roberto Gambino, Maria Grazia De Cesaris, Giovanni Garbarino, Giovanni Camussi, Gianfranco Pagano, Luigi Pegoraro

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Figure 2

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Effects of dm-LDL and n-LDL on the cell cycle. HUVECs, unstimulated (a) ...
Effects of dm-LDL and n-LDL on the cell cycle. HUVECs, unstimulated (a) or stimulated for 12 hours with n-LDL (b) or dm-LDL (c), were harvested and fixed with ethanol. DNA was stained with propidium iodide, and fluorescence was evaluated by flow cytometry using FACScan equipment (Becton Dickinson Immunocytometry Systems, San Jose, California, USA). Percentage of cells in each phase is shown, as determined by ModFit LT software (Verity Software House Inc., Topsham, Maine, USA). Similar results were obtained in three different individual experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 1 patents
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