Document Detail

Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation.
MedLine Citation:
PMID:  20051384     Owner:  NLM     Status:  MEDLINE    
AIMS: Phosphatase and tensin homolog (PTEN) is implicated as a negative regulator of vascular smooth muscle cell (SMC) proliferation and injury-induced vascular remodelling. We tested if selective depletion of PTEN only in SMC is sufficient to promote SMC phenotypic modulation, cytokine production, and enhanced neointima formation.
METHODS AND RESULTS: Smooth muscle marker expression and induction of pro-inflammatory cytokines were compared in cultured SMC expressing control or PTEN-specific shRNA. Compared with controls, PTEN-deficient SMC exhibited increased phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signalling and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity, reduced expression of SM markers (SM-alpha-actin and calponin), and increased production of stromal cell-derived factor-1alpha (SDF-1alpha), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and chemokine (C-X-C motif) ligand 1 (KC/CXCL1) under basal conditions. PI3K/Akt or mTOR inhibition reversed repression of SM marker expression, whereas PI3K/Akt or NF-kappaB inhibition blocked cytokine induction mediated by PTEN depletion. Carotid ligation in mice with genetic reduction of PTEN specifically in SMC (SMC-specific PTEN heterozygotes) resulted in enhanced neointima formation, increased SMC hyperplasia, reduced SM-alpha-actin and calponin expression, and increased NF-kappaB and cytokine expression compared with wild-types. Lesion formation in SMC-specific heterozygotes was similar to lesion formation in global PTEN heterozygotes, indicating that inactivation of PTEN exclusively in SMC is sufficient to induce considerable increases in neointima formation.
CONCLUSION: PTEN activation specifically in SMC is a common upstream regulator of multiple downstream events involved in pathological vascular remodelling, including proliferation, de-differentiation, and production of multiple cytokines.
Seth B Furgeson; Peter A Simpson; Insun Park; Vicki Vanputten; Henrick Horita; Christopher D Kontos; Raphael A Nemenoff; Mary C M Weiser-Evans
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-01-05
Journal Detail:
Title:  Cardiovascular research     Volume:  86     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-04-20     Completed Date:  2010-07-26     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  274-82     Citation Subset:  IM    
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
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MeSH Terms
Carotid Artery Injuries / enzymology*,  genetics,  immunology,  pathology
Cell Dedifferentiation
Cell Proliferation*
Cells, Cultured
Cytokines / metabolism
Disease Models, Animal
Inflammation / enzymology*,  genetics,  immunology,  pathology
Inflammation Mediators / metabolism
Intracellular Signaling Peptides and Proteins / metabolism
Mice, Knockout
Muscle, Smooth, Vascular / enzymology*,  immunology,  pathology
Myocytes, Smooth Muscle / enzymology*,  immunology,  pathology
NF-kappa B / metabolism
PTEN Phosphohydrolase / deficiency*,  genetics
Phosphatidylinositol 3-Kinases / metabolism
Protein-Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
Signal Transduction
TOR Serine-Threonine Kinases
Tunica Intima / enzymology*,  immunology,  pathology
Grant Support
Reg. No./Substance:
0/Cytokines; 0/Inflammation Mediators; 0/Intracellular Signaling Peptides and Proteins; 0/NF-kappa B; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Serine-Threonine Kinases; EC protein, mouse; EC protein, rat; EC Kinases; EC Proteins c-akt; EC protein, mouse; EC protein, rat; EC Phosphohydrolase

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