PMID- 23860374
OWN - NLM
STAT- MEDLINE
DCOM- 20131122
LR  - 20211203
IS  - 1559-7016 (Electronic)
IS  - 0271-678X (Print)
IS  - 0271-678X (Linking)
VI  - 33
IP  - 10
DP  - 2013 Oct
TI  - TNF-alpha induces phenotypic modulation in cerebral vascular smooth muscle cells: 
      implications for cerebral aneurysm pathology.
PG  - 1564-73
LID - 10.1038/jcbfm.2013.109 [doi]
AB  - Little is known about vascular smooth muscle cell (SMC) phenotypic modulation in 
      the cerebral circulation or pathogenesis of intracranial aneurysms. Tumor 
      necrosis factor-alpha (TNF-alpha) has been associated with aneurysms, but potential 
      mechanisms are unclear. Cultured rat cerebral SMCs overexpressing myocardin 
      induced expression of key SMC contractile genes (SM-alpha-actin, SM-22alpha, smooth 
      muscle myosin heavy chain), while dominant-negative cells suppressed expression. 
      Tumor necrosis factor-alpha treatment inhibited this contractile phenotype and 
      induced pro-inflammatory/matrix-remodeling genes (monocyte chemoattractant 
      protein-1, matrix metalloproteinase-3, matrix metalloproteinase-9, vascular cell 
      adhesion molecule-1, interleukin-1 beta). Tumor necrosis factor-alpha increased 
      expression of KLF4, a known regulator of SMC differentiation. Kruppel-like 
      transcription factor 4 (KLF4) small interfering RNA abrogated TNF-alpha activation of 
      inflammatory genes and suppression of contractile genes. These mechanisms were 
      confirmed in vivo after exposure of rat carotid arteries to TNF-alpha and early on in 
      a model of cerebral aneurysm formation. Treatment with the synthesized TNF-alpha 
      inhibitor 3,6-dithiothalidomide reversed pathologic vessel wall alterations after 
      induced hypertension and hemodynamic stress. Chromatin immunoprecipitation assays 
      in vivo and in vitro demonstrated that TNF-alpha promotes epigenetic changes through 
      KLF4-dependent alterations in promoter regions of myocardin, SMCs, and 
      inflammatory genes. In conclusion, TNF-alpha induces phenotypic modulation of 
      cerebral SMCs through myocardin and KLF4-regulated pathways. These results 
      demonstrate a novel role for TNF-alpha in promoting a 
      pro-inflammatory/matrix-remodeling phenotype, which has important implications 
      for the mechanisms behind intracranial aneurysm formation.
FAU - Ali, Muhammad S
AU  - Ali MS
AD  - Joseph and Marie Field Cerebrovascular Research Laboratory, Division of 
      Neurovascular & Endovascular Surgery, Department of Neurological Surgery, Thomas 
      Jefferson University, Philadelphia, Pennsylvania, USA.
FAU - Starke, Robert M
AU  - Starke RM
FAU - Jabbour, Pascal M
AU  - Jabbour PM
FAU - Tjoumakaris, Stavropoula I
AU  - Tjoumakaris SI
FAU - Gonzalez, L Fernando
AU  - Gonzalez LF
FAU - Rosenwasser, Robert H
AU  - Rosenwasser RH
FAU - Owens, Gary K
AU  - Owens GK
FAU - Koch, Walter J
AU  - Koch WJ
FAU - Greig, Nigel H
AU  - Greig NH
FAU - Dumont, Aaron S
AU  - Dumont AS
LA  - eng
GR  - R01 HL57353/HL/NHLBI NIH HHS/United States
GR  - R01 HL087867/HL/NHLBI NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
GR  - K08NS067072/NS/NINDS NIH HHS/United States
GR  - R01 HL057353/HL/NHLBI NIH HHS/United States
GR  - K08 NS067072/NS/NINDS NIH HHS/United States
GR  - T32 HL007544/HL/NHLBI NIH HHS/United States
GR  - P01 HL07544/HL/NHLBI NIH HHS/United States
GR  - P01 HL091799/HL/NHLBI NIH HHS/United States
GR  - R01 HL098538/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20130717
PL  - United States
TA  - J Cereb Blood Flow Metab
JT  - Journal of cerebral blood flow and metabolism : official journal of the 
      International Society of Cerebral Blood Flow and Metabolism
JID - 8112566
RN  - 0 (3,6'-dithiothalidomide)
RN  - 0 (Genetic Markers)
RN  - 0 (Klf4 protein, rat)
RN  - 0 (Kruppel-Like Factor 4)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Trans-Activators)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (myocardin)
RN  - 4Z8R6ORS6L (Thalidomide)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects/genetics
MH  - Carotid Arteries/drug effects/pathology
MH  - Cell Differentiation/drug effects/genetics
MH  - Cells, Cultured
MH  - Circle of Willis/drug effects/metabolism/*pathology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Epigenesis, Genetic
MH  - Genetic Markers/drug effects
MH  - Intracranial Aneurysm/genetics/immunology/*pathology
MH  - Kruppel-Like Factor 4
MH  - Kruppel-Like Transcription Factors/genetics/physiology
MH  - Muscle, Smooth, Vascular/drug effects/metabolism/*pathology
MH  - Nuclear Proteins/genetics
MH  - Promoter Regions, Genetic
MH  - Rats
MH  - Thalidomide/analogs & derivatives/pharmacology
MH  - Trans-Activators/genetics
MH  - Transcriptome
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors/*pharmacology/physiology
PMC - PMC3790924
EDAT- 2013/07/19 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/10/01
CRDT- 2013/07/18 06:00
PHST- 2013/03/25 00:00 [received]
PHST- 2013/05/30 00:00 [revised]
PHST- 2013/06/04 00:00 [accepted]
PHST- 2013/07/18 06:00 [entrez]
PHST- 2013/07/19 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - jcbfm2013109 [pii]
AID - 10.1038/jcbfm.2013.109 [doi]
PST - ppublish
SO  - J Cereb Blood Flow Metab. 2013 Oct;33(10):1564-73. doi: 10.1038/jcbfm.2013.109. 
      Epub 2013 Jul 17.