PMID- 23418090
OWN - NLM
STAT- MEDLINE
DCOM- 20130606
LR  - 20211021
IS  - 1522-1504 (Electronic)
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 304
IP  - 8
DP  - 2013 Apr 15
TI  - Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle 
      cells by endothelin-1.
PG  - L549-61
LID - 10.1152/ajplung.00081.2012 [doi]
AB  - Numerous cellular responses to hypoxia are mediated by the transcription factor 
      hypoxia-inducible factor-1 (HIF-1). HIF-1 plays a central role in the 
      pathogenesis of hypoxic pulmonary hypertension. Under certain conditions, HIF-1 
      may utilize feedforward mechanisms to amplify its activity. Since hypoxia 
      increases endothelin-1 (ET-1) levels in the lung, we hypothesized that during 
      moderate, prolonged hypoxia ET-1 might contribute to HIF-1 signaling in pulmonary 
      arterial smooth muscle cells (PASMCs). Primary cultures of rat PASMCs were 
      treated with ET-1 or exposed to moderate, prolonged hypoxia (4% O(2) for 60 h). 
      Levels of the oxygen-sensitive HIF-1alpha subunit and expression of HIF target genes 
      were increased in both hypoxic cells and cells treated with ET-1. Both hypoxia 
      and ET-1 also increased HIF-1alpha mRNA expression and decreased mRNA and protein 
      expression of prolyl hydroxylase 2 (PHD2), which is the protein responsible for 
      targeting HIF-1alpha for O(2)-dependent degradation. The induction of HIF-1alpha by 
      moderate, prolonged hypoxia was blocked by BQ-123, an antagonist of ET-1 receptor 
      subtype A. The effects of ET-1 were mediated by increased intracellular calcium, 
      generation of reactive oxygen species, and ERK1/2 activation. Neither ET-1 nor 
      moderate hypoxia induced the expression of HIF-1alpha or HIF target genes in aortic 
      smooth muscle cells. These results suggest that ET-1 induces a PASMC-specific 
      increase in HIF-1alpha levels by upregulation of HIF-1alpha synthesis and downregulation 
      of PHD2-mediated degradation, thereby amplifying the induction of HIF-1alpha in 
      PASMCs during moderate, prolonged hypoxia.
FAU - Pisarcik, Sarah
AU  - Pisarcik S
AD  - Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School 
      of Medicine, Baltimore, MD 21224, USA.
FAU - Maylor, Julie
AU  - Maylor J
FAU - Lu, Wenju
AU  - Lu W
FAU - Yun, Xin
AU  - Yun X
FAU - Undem, Clark
AU  - Undem C
FAU - Sylvester, J T
AU  - Sylvester JT
FAU - Semenza, Gregg L
AU  - Semenza GL
FAU - Shimoda, Larissa A
AU  - Shimoda LA
LA  - eng
GR  - HL67191/HL/NHLBI NIH HHS/United States
GR  - HL67919/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130215
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (Endothelin A Receptor Antagonists)
RN  - 0 (Endothelin-1)
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Peptides, Cyclic)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.11.29 (Egln1 protein, rat)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - S2A8YZM151 (cyclo(Trp-Asp-Pro-Val-Leu))
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Calcium/metabolism
MH  - Cell Hypoxia/genetics/physiology
MH  - Cells, Cultured
MH  - Endothelin A Receptor Antagonists
MH  - Endothelin-1/*pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Gene Expression/drug effects
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases
MH  - Male
MH  - Myocytes, Smooth Muscle/drug effects/metabolism
MH  - Peptides, Cyclic/pharmacology
MH  - Procollagen-Proline Dioxygenase/genetics/metabolism
MH  - Pulmonary Artery/cytology/*drug effects/*metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Reactive Oxygen Species/metabolism
PMC - PMC3625988
EDAT- 2013/02/19 06:00
MHDA- 2013/06/07 06:00
PMCR- 2014/04/15
CRDT- 2013/02/19 06:00
PHST- 2013/02/19 06:00 [entrez]
PHST- 2013/02/19 06:00 [pubmed]
PHST- 2013/06/07 06:00 [medline]
PHST- 2014/04/15 00:00 [pmc-release]
AID - ajplung.00081.2012 [pii]
AID - L-00081-2012 [pii]
AID - 10.1152/ajplung.00081.2012 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2013 Apr 15;304(8):L549-61. doi: 
      10.1152/ajplung.00081.2012. Epub 2013 Feb 15.