PMID- 21205918
OWN - NLM
STAT- MEDLINE
DCOM- 20110519
LR  - 20110323
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 337
IP  - 1
DP  - 2011 Apr
TI  - Tumor necrosis factor-alpha accelerates the calcification of human aortic valve 
      interstitial cells obtained from patients with calcific aortic valve stenosis via 
      the BMP2-Dlx5 pathway.
PG  - 16-23
LID - 10.1124/jpet.110.177915 [doi]
AB  - Calcific aortic valve stenosis (CAS) is the most frequent heart valve disease in 
      the elderly, accompanied by valve calcification. Tumor necrosis factor-alpha (TNF-alpha), 
      a pleiotropic cytokine secreted mainly from macrophages, has been detected in 
      human calcified valves. However, the role of TNF-alpha in valve calcification remains 
      unclear. To clarify whether TNF-alpha accelerates the calcification of aortic valves, 
      we investigated the effect of TNF-alpha on human aortic valve interstitial cells 
      (HAVICs) obtained from patients with CAS (CAS group) and with aortic 
      regurgitation or aortic dissection having a noncalcified aortic valve (control 
      group). HAVICs (2 x 10(4)) were cultured in a 12-well dish in Dulbecco's modified 
      Eagle's medium with 10% fetal bovine serum. The medium containing TNF-alpha (30 
      ng/ml) was replenished every 3 days after the cells reached confluence. TNF-alpha 
      significantly accelerated the calcification and alkaline phosphatase (ALP) 
      activity of HAVICs from CAS but not the control group after 12 days of culture. 
      Furthermore, gene expression of calcigenic markers, ALP, bone morphogenetic 
      protein 2 (BMP2), and distal-less homeobox 5 (Dlx5) were significantly increased 
      after 6 days of TNF-alpha treatment in the CAS group but not the control group. 
      Dorsomorphin, an inhibitor of mothers against decapentaplegic homologs (Smads) 
      1/5/8 phosphorylation, significantly inhibited the enhancement of TNF-alpha-induced 
      calcification, ALP activity, Smad phosphorylation, and Dlx5 gene expression of 
      HAVICs from the CAS group. These results suggest that HAVICs from the CAS group 
      have greater sensitivity to TNF-alpha, which accelerates the calcification of aortic 
      valves via the BMP2-Dlx5 pathway.
FAU - Yu, Zaiqiang
AU  - Yu Z
AD  - Department of Pharmacology, Hirosaki University Graduate School of Medicine, 
      Hirosaki, Japan.
FAU - Seya, Kazuhiko
AU  - Seya K
FAU - Daitoku, Kazuyuki
AU  - Daitoku K
FAU - Motomura, Shigeru
AU  - Motomura S
FAU - Fukuda, Ikuo
AU  - Fukuda I
FAU - Furukawa, Ken-Ichi
AU  - Furukawa K
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101230
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (BMP2 protein, human)
RN  - 0 (Bone Morphogenetic Protein 2)
RN  - 0 (DLX5 protein, human)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.1.3.1 (Alkaline Phosphatase)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Alkaline Phosphatase/biosynthesis/metabolism
MH  - Aortic Valve/metabolism/pathology
MH  - Aortic Valve Stenosis/enzymology/*metabolism/pathology
MH  - Bone Morphogenetic Protein 2/*physiology
MH  - Calcinosis/enzymology/*metabolism/pathology
MH  - Cells, Cultured
MH  - Female
MH  - Homeodomain Proteins/*physiology
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Signal Transduction/drug effects/physiology
MH  - Transcription Factors/*physiology
MH  - Tumor Necrosis Factor-alpha/*toxicity
EDAT- 2011/01/06 06:00
MHDA- 2011/05/20 06:00
CRDT- 2011/01/06 06:00
PHST- 2011/01/06 06:00 [entrez]
PHST- 2011/01/06 06:00 [pubmed]
PHST- 2011/05/20 06:00 [medline]
AID - jpet.110.177915 [pii]
AID - 10.1124/jpet.110.177915 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2011 Apr;337(1):16-23. doi: 10.1124/jpet.110.177915. Epub 
      2010 Dec 30.