Document Detail

Growth suppression of human coronary vascular smooth muscle cells by gene transfer of the transcription factor E2F-1.
MedLine Citation:
PMID:  11157693     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: The transcription factor E2F-1 promotes S-phase entry and death in transformed cells and primary cardiomyocytes. We tested the hypothesis that overexpression of E2F-1 forces growth-arrested human coronary vascular smooth muscle cells (VSMCs) to enter the S phase, undergo apoptosis, and thereby regulate VSMC growth. METHODS AND RESULTS: Early-passage (</=5 passages) coronary VSMCs were transduced at an MOI of 100 with a recombinant adenovirus encoding human E2F-1. E2F-1 expression was observed by immunohistochemistry as early as 6 to 8 hours after exposure of the VSMCs to Ad.E2F-1 but not to the control vector Ad.RR. When cells were kept in growth-arrest medium, 40% of Ad.E2F-1-treated VSMCs entered the S phase by 96 hours, whereas the percentage remained <5% in Ad.RR-treated cells. Transition to the S phase in the E2F-1-transduced VSMCs was followed by apoptosis, as reflected by chromatin condensation, membrane blebbing, cell detachment, and loss of mitochondrial membrane integrity. E2F-1 overexpression resulted in positive dUTP nick end-labeling mediated by terminal deoxynucleotidyl transferase, associated with a robust increase in caspase 3-like activity. Four days after infection with Ad.E2F-1, the fraction of hypodiploid VSMCs in subG(1) increased to 75%. At 7 days, gene transfer of E2F-1 had completely suppressed the growth of VSMCs, whereas the number of Ad.RR-infected cells had increased >8 times. CONCLUSIONS:Overexpression of the transcription factor E2F-1 regulates growth of human coronary VSMCs by forcing the cells to enter the S phase and then to die. Cell death appears to involve caspase 3-like activity, which, in the VSMCs, is markedly increased by overexpression of E2F-1.
H S Shelat; T J Liu; D L Hickman-Bick; M K Barnhart; T Vida; P M Dillard; J T Willerson; P Zoldhelyi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  103     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2001 Jan 
Date Detail:
Created Date:  2001-02-22     Completed Date:  2001-04-26     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  407-14     Citation Subset:  IM    
Wafic Said Molecular Cardiology and Gene Therapy Research Laboratory, Texas Heart Institute, Houston, TX 77030, USA.
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MeSH Terms
Adenoviridae / genetics
Carrier Proteins*
Caspase 3
Caspases / biosynthesis
Cell Count
Cell Cycle Proteins*
Cells, Cultured
Coronary Vessels / cytology,  growth & development*
DNA-Binding Proteins*
E2F Transcription Factors
E2F1 Transcription Factor
Enzyme Induction
Flow Cytometry
Genetic Vectors
In Situ Nick-End Labeling
Muscle Development*
Muscle, Smooth, Vascular / cytology,  growth & development*
Retinoblastoma-Binding Protein 1
S Phase
Time Factors
Transcription Factor DP1
Transcription Factors / biosynthesis,  genetics*,  pharmacology
Grant Support
1RO1-HL-50179-01/HL/NHLBI NIH HHS; 1RO1-HL-54839-01/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Carrier Proteins; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/E2F Transcription Factors; 0/E2F1 Transcription Factor; 0/E2F1 protein, human; 0/Retinoblastoma-Binding Protein 1; 0/Transcription Factor DP1; 0/Transcription Factors; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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