High glucose decreases endothelial cell proliferation via the extracellular signal regulated kinase/p15(INK4b) pathway.
High glucose inhibits endothelial cell proliferation. Thus, we studied cyclin-dependent kinase inhibitor p15(INK4b) in high glucose-induced effects in human umbilical endothelial cells at 24h. High glucose decreased cell proliferation while arresting cells in G(0)/G(1) phase of the cell cycle. High glucose increased phospho-extracellular signal regulated kinase (ERK)1/2, p15(INK4b) protein and mRNA expression. High glucose-inhibited cell proliferation was attenuated by antisense p15(INK4b) oligonucleotide. Moreover, PD98059 attenuated high glucose-induced p15(INK4b) protein expression. High glucose increased transforming growth factor-beta (TGF-beta) gene transcriptional activity and mRNA expression. However, neither SB431542 (type I TGF-beta receptor blocker) nor TGF-beta1 antibody affected high glucose-induced p15(INK4b) protein expression. Additionally, N-acetylcysteine (an antioxidant) attenuated high glucose-induced growth arrest and p15(INK4b) protein expression. Thus, high glucose-induced growth arrest is dependent on p15(INK4b) and oxidative stress in endothelial cells. Moreover, high glucose-induced p15(INK4b) protein expression is dependent on ERK1/2 and oxidative stress.
Chen
Yen-Hui
YH
Graduate Institute of Medicine, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Guh
Jinn-Yuh
JY
Chuang
Tsai-Der
TD
Chen
Hung-Chun
HC
Chiou
Shean-Jaw
SJ
Huang
Jau-Shyang
JS
Yang
Yu-Lin
YL
Chuang
Lea-Yea
LY
D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*
C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose