PMID- 18506850
OWN - NLM
STAT- MEDLINE
DCOM- 20080826
LR  - 20131121
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 48
IP  - 1
DP  - 2008 Jul
TI  - Adenosine-dependent activation of hypoxia-inducible factor-1 induces late 
      preconditioning in liver cells.
PG  - 230-9
LID - 10.1002/hep.22249 [doi]
AB  - The cellular mechanisms by which ischemic preconditioning increases liver 
      tolerance to ischemia/reperfusion injury are still poorly understood. This study 
      investigated the role of the hypoxia-inducible factor-1 (HIF-1) in the protection 
      associated with the late phase of liver preconditioning. Late preconditioning was 
      induced in primary cultured rat hepatocytes by a transient (10 minute) hypoxic 
      stress or by 15 minutes incubation with the adenosine A(2A) receptors agonist 
      CGS21680 24 hours before exposure to 90 minutes of hypoxia in a serum-free 
      medium. Late preconditioning induced the nuclear translocation of HIF-1 and the 
      expression of carbonic anhydrase IX (CAIX), a HIF-1-regulated transmembrane 
      enzyme that catalyzes bicarbonate production. Such effects were associated with 
      prevention of hepatocyte killing by hypoxia and the amelioration of intracellular 
      acidosis and Na+ accumulation. The inhibition of PKC-mediated and 
      PI3-kinase-mediated signals with, respectively, chelerythrine and wortmannin 
      abolished HIF-1 activation and blocked both CAIX expression and the protective 
      action of late preconditioning. CAIX expression was also prevented by interfering 
      with the transcriptional activity of HIF-1 using a dominant negative HIF-1beta 
      subunit. The inhibition of CAIX with acetazolamide or the block of bicarbonate 
      influx with disodium-4-acetamido-4'-isothiocyanato-stilben-2,2'-disulfonate also 
      reverted the protective effects of late preconditioning on intracellular acidosis 
      and Na+ accumulation. CONCLUSION: The stimulation of adenosine A(2A) receptors 
      induced late preconditioning in liver cells through the activation of HIF-1. 
      HIF-1-induced expression of CAIX increases hepatocyte tolerance to ischemia by 
      maintaining intracellular Na+ homeostasis. These observations along with the 
      importance of HIF-1 in regulating cell survival indicates HIF-1 activation as a 
      possible key event in liver protection by late preconditioning.
FAU - Alchera, Elisa
AU  - Alchera E
AD  - Dipartimento di Scienze Mediche, Universita "A. Avogadro", Novara, Italy.
FAU - Tacchini, Lorenza
AU  - Tacchini L
FAU - Imarisio, Chiara
AU  - Imarisio C
FAU - Dal Ponte, Caterina
AU  - Dal Ponte C
FAU - De Ponti, Cristina
AU  - De Ponti C
FAU - Gammella, Elena
AU  - Gammella E
FAU - Cairo, Gaetano
AU  - Cairo G
FAU - Albano, Emanuele
AU  - Albano E
FAU - Carini, Rita
AU  - Carini R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Adenosine A2 Receptor Agonists)
RN  - 0 (Culture Media, Serum-Free)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Phenethylamines)
RN  - 0 (Purinergic P1 Receptor Agonists)
RN  - 0 (Receptor, Adenosine A2A)
RN  - 0 (Receptors, Purinergic P1)
RN  - 120225-54-9 (2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine)
RN  - EC 4.2.1.- (Carbonic Anhydrase IV)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - Adenosine/analogs & derivatives/*metabolism/pharmacology
MH  - Adenosine A2 Receptor Agonists
MH  - Animals
MH  - Biological Transport
MH  - Carbonic Anhydrase IV/metabolism
MH  - Cell Hypoxia/physiology
MH  - Cell Nucleus/metabolism
MH  - Cells, Cultured
MH  - Culture Media, Serum-Free
MH  - Cytoprotection
MH  - Hepatocytes/drug effects/metabolism/*physiology
MH  - Hypoxia-Inducible Factor 1/*metabolism
MH  - *Ischemic Preconditioning
MH  - Liver/*blood supply
MH  - Male
MH  - Phenethylamines/pharmacology
MH  - Purinergic P1 Receptor Agonists
MH  - Rats
MH  - Rats, Wistar
MH  - Receptor, Adenosine A2A/*metabolism
MH  - Receptors, Purinergic P1/*metabolism
MH  - Time Factors
EDAT- 2008/05/29 09:00
MHDA- 2008/08/30 09:00
CRDT- 2008/05/29 09:00
PHST- 2008/05/29 09:00 [pubmed]
PHST- 2008/08/30 09:00 [medline]
PHST- 2008/05/29 09:00 [entrez]
AID - 10.1002/hep.22249 [doi]
PST - ppublish
SO  - Hepatology. 2008 Jul;48(1):230-9. doi: 10.1002/hep.22249.