PMID- 27432037
OWN - NLM
STAT- MEDLINE
DCOM- 20170505
LR  - 20211204
IS  - 1538-2990 (Electronic)
IS  - 0002-9629 (Print)
IS  - 0002-9629 (Linking)
VI  - 352
IP  - 1
DP  - 2016 Jul
TI  - Time-dependent PPARgamma Modulation of HIF-1alpha Signaling in Hypoxic Pulmonary Artery 
      Smooth Muscle Cells.
PG  - 71-9
LID - S0002-9629(15)41038-9 [pii]
LID - 10.1016/j.amjms.2016.03.019 [doi]
AB  - BACKGROUND: Pathogenesis of pulmonary hypertension is complex and involves 
      activation of the transcription factor, hypoxia-inducible factor-1 (HIF-1) that 
      shifts cellular metabolism from aerobic respiration to glycolysis, in part, by 
      increasing the expression of its downstream target pyruvate dehydrogenase 
      kinase-1 (PDK-1), thereby promoting a proliferative, apoptosis-resistant 
      phenotype in pulmonary vascular cells. Activation of the nuclear hormone 
      transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), 
      attenuates pulmonary hypertension and pulmonary artery smooth muscle cell (PASMC) 
      proliferation. In the current study, we determined whether PPARgamma inhibits HIF-1alpha 
      and PDK-1 expression in human PASMCs. METHODS: HPASMCs were exposed to normoxia 
      (21% O2) or hypoxia (1% O2) for 2-72 hours +/- treatment with the PPARgamma-ligand, 
      rosiglitazone (RSG, 10muM). RESULTS: Compared to normoxia, HIF-1alpha mRNA levels were 
      elevated in HPASMC at 2 hours hypoxia and reduced to baseline levels by 24-72 
      hours. HIF-1alpha protein levels increased following 4 and 8 hours of hypoxia and 
      returned to baseline levels by 24 and 72 hours. PDK-1 protein levels increased 
      following 24 hours hypoxia and remained elevated by 72 hours. RSG treatment at 
      the onset of hypoxia attenuated HIF-1alpha protein and PDK-1 mRNA and protein levels 
      at 4, 8 and 24 hours of hypoxia, respectively. However, RSG treatment during 
      final 24 hours of 72-hour hypoxia, an intervention that inhibits HPASMC 
      proliferation, failed to prevent hypoxia-induced PDK-1 expression. CONCLUSION: 
      Hypoxia causes transient activation of HPASMC HIF-1alpha that is attenuated by RSG 
      treatment initiated at hypoxia onset. These findings provide novel evidence that 
      PPARgamma modulates fundamental and acute cellular responses to hypoxia through both 
      HIF-1-dependent and HIF-1-independent mechanisms.
CI  - Published by Elsevier Inc.
FAU - Blum, Justine I
AU  - Blum JI
AD  - Emory University School of Medicine, Atlanta, Georgia.
FAU - Bijli, Kaiser M
AU  - Bijli KM
AD  - Emory University School of Medicine, Atlanta, Georgia; Emory Division of 
      Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center, 
      Decatur, Georgia.
FAU - Murphy, Tamara C
AU  - Murphy TC
AD  - Emory University School of Medicine, Atlanta, Georgia; Emory Division of 
      Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center, 
      Decatur, Georgia.
FAU - Kleinhenz, Jennifer M
AU  - Kleinhenz JM
AD  - Emory University School of Medicine, Atlanta, Georgia; Emory Division of 
      Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center, 
      Decatur, Georgia.
FAU - Hart, C Michael
AU  - Hart CM
AD  - Emory University School of Medicine, Atlanta, Georgia; Emory Division of 
      Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center, 
      Decatur, Georgia. Electronic address: Michael.hart3@va.gov.
LA  - eng
GR  - I01 BX001910/BX/BLRD VA/United States
GR  - R01 HL102167/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20160404
PL  - United States
TA  - Am J Med Sci
JT  - The American journal of the medical sciences
JID - 0370506
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Ligands)
RN  - 0 (PPAR gamma)
RN  - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)
RN  - 0 (Thiazolidinediones)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Cell Proliferation/drug effects
MH  - Humans
MH  - Hypoxia/physiopathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*genetics/metabolism
MH  - Ligands
MH  - Myocytes, Smooth Muscle/physiology
MH  - PPAR gamma/*genetics/metabolism
MH  - Protein Serine-Threonine Kinases/genetics/metabolism
MH  - Pulmonary Artery/physiopathology
MH  - Pyruvate Dehydrogenase Acetyl-Transferring Kinase
MH  - Rosiglitazone
MH  - *Signal Transduction
MH  - Thiazolidinediones/*pharmacology
PMC - PMC5483378
MID - NIHMS867878
OTO - NOTNLM
OT  - HIF-1alpha
OT  - PDK-1
OT  - PPARgamma
OT  - Pulmonary hypertension
OT  - Vascular smooth muscle cell
COIS- The authors have no conflicts of interest to disclose.
EDAT- 2016/07/20 06:00
MHDA- 2017/05/06 06:00
PMCR- 2017/06/25
CRDT- 2016/07/20 06:00
PHST- 2015/11/16 00:00 [received]
PHST- 2016/03/01 00:00 [revised]
PHST- 2016/03/30 00:00 [accepted]
PHST- 2016/07/20 06:00 [entrez]
PHST- 2016/07/20 06:00 [pubmed]
PHST- 2017/05/06 06:00 [medline]
PHST- 2017/06/25 00:00 [pmc-release]
AID - S0002-9629(15)41038-9 [pii]
AID - 10.1016/j.amjms.2016.03.019 [doi]
PST - ppublish
SO  - Am J Med Sci. 2016 Jul;352(1):71-9. doi: 10.1016/j.amjms.2016.03.019. Epub 2016 
      Apr 4.