STAT5 activation induced by diabetic LDL depends on LDL glycation and occurs via src kinase activity.
Advanced glycation end products (AGEs) have been implicated in the accelerated vascular injury occurring in diabetes. We recently reported that LDL prepared from type 2 diabetic patients (dm-LDL), but not normal LDL (n-LDL) triggered signal transducers and activators of transcription STAT5 activation and p21(waf) expression in endothelial cells (ECs). The aims of the present study were to investigate the role of LDL glycation in dm-LDL- mediated signals and to analyze the molecular mechanisms leading to STAT5 activation. We found that glycated LDL (gly-LDL) triggered STAT5 activation, the formation of a prolactin inducible element (PIE)-binding complex containing STAT5, and increased p21(waf) expression through the activation of the receptor for AGE (RAGE). We also demonstrated that dm-LDL and gly-LDL, but not n-LDL treatment induced the formation of a stable complex containing the activated STAT5 and RAGE. Moreover, gly-LDL triggered src but not JAK2 kinase activity. Pretreatment with the src kinase inhibitor PP1 abrogated both STAT5 activation and the expression of p21(waf) induced by gly-LDL. Consistently, gly-LDL failed to activate STAT5 in src(-/-) fibroblasts. Collectively, our results provide evidence for the role of glycation in dm-LDL-mediated effects and for a specific role of src kinase in STAT5-dependent p21(waf) expression.
Brizzi
Maria Felice
MF
Department of Internal Medicine, University of Torino, Torino, Italy.
Dentelli
Patrizia
P
Gambino
Roberto
R
Cabodi
Sara
S
Cassader
Maurizio
M
Castelli
Ada
A
Defilippi
Paola
P
Pegoraro
Luigi
L
Pagano
Gianfranco
G
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood*; D004730:Endothelium, Vascular / Q000166:cytology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood*; D008894:Milk Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D012016:Reference Values; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014471:Umbilical Veins; D019061:src-Family Kinases / Q000378:metabolism*
D004268:DNA-Binding Proteins; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; D008894:Milk Proteins; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019061:src-Family Kinases