PMID- 20709868
OWN - NLM
STAT- MEDLINE
DCOM- 20101130
LR  - 20200930
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 299
IP  - 4
DP  - 2010 Oct
TI  - Tumor necrosis factor inhibitors as novel therapeutic tools for vascular 
      remodeling diseases.
PG  - H995-1001
LID - 10.1152/ajpheart.00562.2010 [doi]
AB  - Vascular remodeling diseases (VRDs) are characterized by enhanced inflammation 
      and proliferative and apoptosis-resistant vascular smooth muscle cells (VSMCs). 
      The sustainability of this phenotype has been attributed in part to the 
      activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). There 
      is evidence that circulating cytokines can act as HIF-1 activators in a variety 
      of tissues, including VSMCs. Increased circulating tumor necrosis factor (TNF) 
      levels have been associated with vascular diseases, but the mechanisms involved 
      remain unknown. We hypothesized that increased circulating levels of TNF promotes 
      VRDs by the activation of HIF-1, resulting in VSMC proliferation and resistance 
      to apoptosis. Circulating TNF levels were significantly increased in patients 
      with vascular diseases (n = 19) compared with healthy donors (n = 15). Using 
      human carotid artery smooth muscle cells (CASMCs), we demonstrated that TNF (100 
      ng/ml) activates HIF-1 (HIF-1alpha expression), leading to increased CASMC 
      proliferation (Ki-67 and PCNA staining) and resistance to mitochondrial-dependent 
      apoptosis [tetramethylrhodamine methyl ester perchlorate (TMRM), terminal 
      deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL), annexin-V 
      staining]. In vivo, TNF inhibition using polyethylene glycol coupled with TNF 
      membrane receptor 1 (PEGsTNFR1), a soluble TNF receptor inhibiting circulating 
      TNF, prevented carotid artery postinjury media remodeling and neointima 
      development in rats. This effect was associated with lowered HIF-1 activation and 
      decreased CASMC proliferation. In conclusion, we demonstrate for the first time 
      that the inhibition of the TNF/Akt/HIF-1 axis prevents vascular remodeling. TNF 
      inhibitors may therefore represent new and interesting therapeutic tools against 
      VRDs.
FAU - Lambert, Caroline M
AU  - Lambert CM
AD  - Centre de recherche du Centre Hospitalier Universitaire de Quebec, L'Hotel-Dieu 
      de Quebec, Faculte de Medecine, Universite Laval, Quebec, Canada.
FAU - Roy, Melanie
AU  - Roy M
FAU - Meloche, Jolyane
AU  - Meloche J
FAU - Robitaille, Genevieve A
AU  - Robitaille GA
FAU - Agharazii, Mohsen
AU  - Agharazii M
FAU - Richard, Darren E
AU  - Richard DE
FAU - Bonnet, Sebastien
AU  - Bonnet S
LA  - eng
GR  - MOP-49609/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100813
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cardiovascular Diseases/*drug therapy/metabolism
MH  - Carotid Arteries/cytology/metabolism
MH  - Case-Control Studies
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/metabolism
MH  - Male
MH  - Muscle, Smooth, Vascular/cytology/metabolism
MH  - Polyethylene Glycols/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/blood/pharmacology
EDAT- 2010/08/17 06:00
MHDA- 2010/12/14 06:00
CRDT- 2010/08/17 06:00
PHST- 2010/08/17 06:00 [entrez]
PHST- 2010/08/17 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
AID - ajpheart.00562.2010 [pii]
AID - 10.1152/ajpheart.00562.2010 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2010 Oct;299(4):H995-1001. doi: 
      10.1152/ajpheart.00562.2010. Epub 2010 Aug 13.