Atheroprotective pulsatile flow induces ubiquitin-proteasome-mediated degradation of programmed cell death 4 in endothelial cells

PLoS One. 2014 Mar 13;9(3):e91564. doi: 10.1371/journal.pone.0091564. eCollection 2014.

Abstract

Objectives: We recently found low level of tumor suppressor programmed cell death 4 (PDCD4) associated with reduced atherosclerotic plaque area (unpublished). We investigated whether atheroprotective unidirectional pulsatile shear stress affects the expression of PDCD4 in endothelial cells.

Methods and results: En face co-immunostaining of the mouse aortic arch revealed a low level of PDCD4 in endothelial cells undergoing pulsatile shear stress. Application of unidirectional pulsatile shear stress to human umbilical vein endothelial cells (HUVECs) decreased PDCD4 protein but not mRNA level. Immunoprecipitation revealed that pulsatile shear stress induced the coupling of ubiquitin with PDCD4 expression. The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway was involved in this ubiquitin-proteasome-mediated degradation of PDCD4. Gain of function and loss of function experiments showed that PDCD4 induced turnover (proliferation and apoptosis) of HUVECs. Low PDCD4 level was associated with reduced proliferation but not apoptosis or phosphorylation of endothelial nitric oxide synthase caused by pulsatile shear stress to help maintain the homeostasis of endothelial cells.

Conclusions: Pulsatile shear stress induces ubiquitin-proteasome-mediated degradation of PDCD4 via a PI3K/Akt pathway in HUVECs. PDCD4 induces turnover (proliferation and apoptosis) of HUVECs. Low PDCD4 level is associated with reduced proliferation for maintenance of HUVEC homeostasis under pulsatile shear stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / metabolism
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology*
  • Atherosclerosis / physiopathology*
  • Cell Proliferation
  • Endothelial Cells / cytology*
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plaque, Atherosclerotic / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Pulsatile Flow*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / physiology*
  • Shear Strength
  • Stress, Mechanical
  • Ubiquitin / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • PDCD4 protein, human
  • Pdcd4 protein, mouse
  • RNA-Binding Proteins
  • Ubiquitin
  • Phosphatidylinositol 3-Kinases
  • Proteasome Endopeptidase Complex

Grants and funding

The study was supported by the National Basic Research Program of China (973 Program, 2010CB732605, 2011CB503906) and the National Natural Science Foundation of China (No. 30970709, 81270404, 81172863). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.