Diabetic LDL inhibits cell-cycle progression via STAT5B and p21(waf).
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.
Brizzi
Maria Felice
MF
Dipartimento di Medicina Interna Università di Torino, Torino, Italy.
Dentelli
Patrizia
P
Pavan
Marzia
M
Rosso
Arturo
A
Gambino
Roberto
R
Grazia De Cesaris
Maria
M
Garbarino
Giovanni
G
Camussi
Giovanni
G
Pagano
Gianfranco
G
Pegoraro
Luigi
L
D000368:Aged; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology / Q000473:pathology; D042846:CDC2-CDC28 Kinases; D016022:Case-Control Studies; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D003925:Diabetic Angiopathies / Q000097:blood / Q000209:etiology / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood* / Q000302:isolation & purification / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008894:Milk Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; D008894:Milk Proteins; D017382:Reactive Oxygen Species; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases