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TRB3 mediates homocysteine-induced inhibition of endothelial cell proliferation

Tong Zou1, Wen-Jing Liu, Shu-De Li

  • 1Department of Cardiology, Beijing Hospital, Beijing, China.

Journal of Cellular Physiology
|September 22, 2011
PubMed

Insights

High homocysteine levels impair endothelial cell proliferation by inducing cell-cycle arrest. Tribbles-related protein 3 (TRB3) plays a key role in this homocysteine-induced endothelial dysfunction.

Area of Science:

  • Cardiovascular Biology
  • Endothelial Cell Function
  • Molecular Mechanisms of Disease

Background:

  • Hyperhomocysteinemia (HHcy) is linked to endothelial dysfunction and atherosclerosis.
  • The precise mechanisms of HHcy-induced endothelial cell injury remain unclear.

Purpose of the Study:

  • To investigate the role of tribbles-related protein 3 (TRB3) in homocysteine-induced cell-cycle arrest in human umbilical vein endothelial cells (HUVECs).

Main Methods:

  • HUVECs were treated with varying concentrations of homocysteine.
  • Cell proliferation was assessed using [(3)H]-thymidine incorporation.
  • Cell-cycle phase distribution and protein levels (p27kip1, TRB3, phosphorylated Akt) were analyzed.
  • TRB3 expression was modulated using siRNA.
  • The involvement of the cAMP/CREB pathway was examined.

Main Results:

  • Homocysteine inhibited HUVEC proliferation and induced G1 cell-cycle arrest, upregulating p27kip1.
  • Homocysteine increased TRB3 expression and decreased Akt phosphorylation without inducing endoplasmic reticulum stress.
  • TRB3 knockdown significantly attenuated homocysteine's inhibitory effect on HUVEC proliferation.
  • Homocysteine-induced TRB3 expression is mediated by the cAMP/CREB pathway.

Conclusions:

  • Tribbles-related protein 3 (TRB3) is a critical mediator of homocysteine-induced cell-cycle arrest in endothelial cells.
  • The cAMP/CREB pathway regulates homocysteine-induced TRB3 expression, contributing to endothelial dysfunction.

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