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High glucose decreases endothelial cell proliferation via the extracellular signal regulated kinase/p15(INK4b)

Yen-Hui Chen1, Jinn-Yuh Guh, Tsai-Der Chuang

  • 1Graduate Institute of Medicine, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Archives of Biochemistry and Biophysics
|June 29, 2007
PubMed

Insights

High glucose impairs endothelial cell proliferation by increasing p15(INK4b) and oxidative stress. This growth arrest is reversible with p15(INK4b) inhibition, highlighting its role in diabetic vascular complications.

Area of Science:

  • Cell Biology
  • Endocrinology
  • Molecular Biology

Background:

  • High glucose levels are known to inhibit endothelial cell proliferation.
  • The role of specific cell cycle regulators, like p15(INK4b), in this process is not fully understood.

Purpose of the Study:

  • To investigate the effect of high glucose on endothelial cell proliferation and the cell cycle.
  • To elucidate the involvement of cyclin-dependent kinase inhibitor p15(INK4b) in high glucose-induced endothelial cell responses.

Main Methods:

  • Human umbilical endothelial cells were treated with high glucose.
  • Cell proliferation, cell cycle phase distribution, and expression of p15(INK4b), phospho-ERK1/2, and TGF-beta were analyzed.
  • Antisense oligonucleotides, PD98059, SB431542, and N-acetylcysteine were used to probe molecular pathways.

Main Results:

  • High glucose decreased cell proliferation and induced G(0)/G(1) cell cycle arrest.
  • High glucose increased phospho-extracellular signal regulated kinase (ERK)1/2, p15(INK4b) protein, and mRNA expression.
  • Antisense p15(INK4b) and N-acetylcysteine (antioxidant) attenuated high glucose-induced growth arrest and p15(INK4b) expression, while PD98059 (ERK inhibitor) also reduced p15(INK4b) levels.

Conclusions:

  • High glucose-induced endothelial cell growth arrest is dependent on p15(INK4b) and oxidative stress.
  • The expression of p15(INK4b) induced by high glucose is mediated by ERK1/2 signaling and oxidative stress.

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