title: Atheroprotective pulsatile flow induces ubiquitin-proteasome-mediated degradation of programmed cell death 4 in endothelial cells.
abstract: OBJECTIVE
  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low level of tumor suppressor programmed cell death 4 (PDCD4) associated with reduced atherosclerotic plaque area (unpublished).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.
  
  
  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.
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ge
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, People's Republic of China.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Emergency, Shandong University Qilu Hospital, Jinan, Shandong, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, People's Republic of China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, People's Republic of China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, People's Republic of China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D050197:Atherosclerosis / Q000503:physiopathology*; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011673:Pulsatile Flow; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D033081:Shear Strength; D013314:Stress, Mechanical; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C114487:PDCD4 protein, human; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D025801:Ubiquitin; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex