PMID- 12829616
OWN - NLM
STAT- MEDLINE
DCOM- 20030822
LR  - 20161124
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 93
IP  - 2
DP  - 2003 Jul 25
TI  - Engineering the response to vascular injury: divergent effects of deregulated 
      E2F1 expression on vascular smooth muscle cells and endothelial cells result in 
      endothelial recovery and inhibition of neointimal growth.
PG  - 162-9
AB  - Tumor necrosis factor-alpha (TNF-alpha) is expressed locally in the vessel wall 
      after angioplasty and induces growth arrest and apoptosis in endothelial cells 
      (ECs), thereby delaying reendothelialization. Prior studies have shown that 
      direct antagonism of TNF-alpha, using a systemically administered soluble 
      receptor, can enhance endothelial recovery and reduce neointimal thickening. 
      These studies have also shown that downregulation of the transcription factor 
      E2F1 was a key mechanism of TNF's effect on ECs. We now show that Ad-E2F1 
      overexpression at sites of balloon injury accelerates functional endothelial 
      recovery, consistent with the prior in vitro findings. Moreover these studies 
      also reveal divergent effects of TNF-alpha and overexpression of E2F1 on ECs 
      versus VSMCs. TNF-alpha exposure of VSMCs had no affect on proliferation or 
      apoptosis, in contrast to the effect seen in ECs. In Ad-E2F1-transduced VSMCs, 
      however, TNF-alpha-induced marked apoptosis in contrast to the survival effect 
      seen in ECs. Finally, these studies suggest that differential activation of 
      NF-kappaB may play a key role in mediating these opposing effects. Nuclear 
      translocation and transcriptional activity of NF-kappaB was markedly attenuated 
      in Ad-E2F1-transduced VSMCs, whereas it remained active in similarly treated ECs 
      when the cells were exposed to TNF-alpha. These studies reveal that 
      overexpression of Ad-E2F1 primes VSMCs to TNF-alpha-induced apoptosis. 
      Furthermore, E2F1 potentiates VSMC death by blocking antiapoptotic signaling 
      pathway through inhibition of NF-kappaB activation. The divergent responses of 
      VSMCs and ECs to E2F1 overexpression provide unique therapeutic possibilities: 
      simultaneously targeting the cell cycle of two different cell types, within same 
      tissue microenvironment resulting in opposite and biologically complimentary 
      effects.
FAU - Goukassian, David A
AU  - Goukassian DA
AD  - Department of Medicine, Division of Cardiovascular Research, St Elizabeth's 
      Medical Center, Boston, Mass, USA.
FAU - Kishore, Raj
AU  - Kishore R
FAU - Krasinski, Kevin
AU  - Krasinski K
FAU - Dolan, Christine
AU  - Dolan C
FAU - Luedemann, Corinne
AU  - Luedemann C
FAU - Yoon, Young-sup
AU  - Yoon YS
FAU - Kearney, Marianne
AU  - Kearney M
FAU - Hanley, Allison
AU  - Hanley A
FAU - Ma, Hong
AU  - Ma H
FAU - Asahara, Takayuki
AU  - Asahara T
FAU - Isner, Jeffrey M
AU  - Isner JM
FAU - Losordo, Douglas W
AU  - Losordo DW
LA  - eng
GR  - HL-53354/HL/NHLBI NIH HHS/United States
GR  - HL-60911/HL/NHLBI NIH HHS/United States
GR  - HL-63414/HL/NHLBI NIH HHS/United States
GR  - HL-63695/HL/NHLBI NIH HHS/United States
GR  - HL-66957/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030626
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (E2F Transcription Factors)
RN  - 0 (E2F1 Transcription Factor)
RN  - 0 (E2F1 protein, human)
RN  - 0 (E2f1 protein, mouse)
RN  - 0 (E2f1 protein, rat)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Nfkbia protein, rat)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Active Transport, Cell Nucleus
MH  - Animals
MH  - Apoptosis
MH  - Carotid Artery Injuries/*metabolism/pathology
MH  - Caspases/metabolism
MH  - Cattle
MH  - *Cell Cycle Proteins
MH  - Cell Division/drug effects/genetics
MH  - Cells, Cultured
MH  - *DNA-Binding Proteins
MH  - Disease Models, Animal
MH  - E2F Transcription Factors
MH  - E2F1 Transcription Factor
MH  - Endothelium, Vascular/cytology/*metabolism
MH  - Gene Expression Regulation
MH  - Genes, Reporter
MH  - Humans
MH  - Hyperplasia/pathology
MH  - I-kappa B Proteins/metabolism
MH  - Mice
MH  - Muscle, Smooth, Vascular/cytology/drug effects/*metabolism/pathology
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/genetics/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recovery of Function
MH  - Transcription Factors/genetics/*metabolism
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - Tunica Intima/*growth & development/injuries/pathology
EDAT- 2003/06/28 05:00
MHDA- 2003/08/23 05:00
CRDT- 2003/06/28 05:00
PHST- 2003/06/28 05:00 [pubmed]
PHST- 2003/08/23 05:00 [medline]
PHST- 2003/06/28 05:00 [entrez]
AID - 01.RES.0000082980.94211.3A [pii]
AID - 10.1161/01.RES.0000082980.94211.3A [doi]
PST - ppublish
SO  - Circ Res. 2003 Jul 25;93(2):162-9. doi: 10.1161/01.RES.0000082980.94211.3A. Epub 
      2003 Jun 26.