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 p21(waf), 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 p21(waf) expression at the transcriptional level. Expression of the dominant-negative form of STAT5B, but not of STAT5A, significantly decreased both p21(waf) 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, p21(waf) 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Arteriosclerosis / blood
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Arteriosclerosis / etiology
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Arteriosclerosis / pathology
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CDC2-CDC28 Kinases*
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Case-Control Studies
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Cell Cycle / drug effects*
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Cell Cycle / physiology
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Cells, Cultured
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / metabolism
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Cyclins / genetics
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Cyclins / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Diabetes Mellitus, Type 2 / blood*
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Diabetic Angiopathies / blood
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Diabetic Angiopathies / etiology
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Diabetic Angiopathies / pathology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / pathology
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Female
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G1 Phase / drug effects
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G1 Phase / physiology
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Gene Expression Regulation / drug effects
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Humans
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Lipoproteins, LDL / blood*
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Lipoproteins, LDL / isolation & purification
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Lipoproteins, LDL / pharmacology*
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Male
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Middle Aged
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Milk Proteins*
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Protein Serine-Threonine Kinases / metabolism
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Reactive Oxygen Species / metabolism
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STAT5 Transcription Factor
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Tumor Suppressor Proteins
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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Lipoproteins, LDL
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Milk Proteins
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Reactive Oxygen Species
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STAT5 Transcription Factor
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STAT5A protein, human
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STAT5B protein, human
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Trans-Activators
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Tumor Suppressor Proteins
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases