PMID- 23582235
OWN - NLM
STAT- MEDLINE
DCOM- 20140120
LR  - 20211021
IS  - 1755-5949 (Electronic)
IS  - 1755-5930 (Print)
IS  - 1755-5930 (Linking)
VI  - 19
IP  - 7
DP  - 2013 Jul
TI  - Zinc promotes the death of hypoxic astrocytes by upregulating hypoxia-induced 
      hypoxia-inducible factor-1alpha expression via poly(ADP-ribose) polymerase-1.
PG  - 511-20
LID - 10.1111/cns.12098 [doi]
AB  - AIM: Pathological release of excess zinc ions has been implicated in ischemic 
      brain cell death. However, the underlying mechanisms remain to be elucidated. In 
      stroke, ischemia-induced zinc release and hypoxia-inducible factor-1 (HIF-1) 
      accumulation concurrently occur in the ischemic tissue. The present study tests 
      the hypothesis that the presence of high intracellular zinc concentration is a 
      major cause of modifications to PARP-1 and HIF-1alpha during hypoxia, which 
      significantly contributes to cell death during ischemia. METHODS: Primary 
      cortical astrocytes and C8-D1A cells were exposed to different concentrations of 
      zinc chloride. Cell death rate and protein expression of HIF-1 and 
      Poly(ADP-ribose) polymerase (PARP)-1 were examined after 3-h hypoxic treatment. 
      RESULTS: Although 3-h hypoxia or 100 muM of zinc alone did not induce noticeable 
      cytotoxicity, their combination led to a dramatic increase in astrocytic cell 
      death in a zinc-concentration-dependent manner. Exposure of astrocytes to hypoxia 
      for 3 h remarkably increased the levels of intracellular zinc and HIF-1alpha protein, 
      which was further augmented by added exogenous zinc. Notably, HIF-1alpha knockdown 
      blocked zinc-induced astrocyte death. Moreover, knockdown of PARP-1, another 
      important protein in the response of hypoxia, attenuated the overexpression of 
      HIF-1alpha and reduced the cell death rate. CONCLUSIONS: Our studies show that zinc 
      promotes hypoxic cell death through overexpression of the hypoxia response factor 
      HIF-1alpha via the cell fate determine factor PARP-1 modification, which provides a 
      novel mechanism for zinc-mediated ischemic brain injury.
CI  - (c) 2013 John Wiley & Sons Ltd.
FAU - Pan, Rong
AU  - Pan R
AD  - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences 
      Center, Albuquerque, NM 87131, USA.
FAU - Chen, Chen
AU  - Chen C
FAU - Liu, Wen-Lan
AU  - Liu WL
FAU - Liu, Ke-Jian
AU  - Liu KJ
LA  - eng
GR  - P20RR15636/RR/NCRR NIH HHS/United States
GR  - P30GM103400/GM/NIGMS NIH HHS/United States
GR  - R01AG031725/AG/NIA NIH HHS/United States
GR  - P20 RR015636/RR/NCRR NIH HHS/United States
GR  - R01 AG031725/AG/NIA NIH HHS/United States
GR  - R01 ES021100/ES/NIEHS NIH HHS/United States
GR  - P30 GM103400/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130413
PL  - England
TA  - CNS Neurosci Ther
JT  - CNS neuroscience & therapeutics
JID - 101473265
RN  - 0 (FluoZin-3)
RN  - 0 (Fluorescent Dyes)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Polycyclic Compounds)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.4.2.30 (Parp1 protein, rat)
RN  - EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Astrocytes/*drug effects
MH  - Blotting, Western
MH  - Cell Death/drug effects
MH  - Cell Hypoxia/*drug effects
MH  - Cell Line
MH  - Data Interpretation, Statistical
MH  - Fluorescent Dyes
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis/genetics
MH  - Poly (ADP-Ribose) Polymerase-1
MH  - Poly(ADP-ribose) Polymerases/genetics/*metabolism
MH  - Polycyclic Compounds
MH  - RNA, Small Interfering/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Up-Regulation
MH  - Zinc/*pharmacology
PMC - PMC3681853
MID - NIHMS453745
COIS- The authors declare no conflict of interest.
EDAT- 2013/04/16 06:00
MHDA- 2014/01/21 06:00
PMCR- 2013/04/13
CRDT- 2013/04/16 06:00
PHST- 2013/01/02 00:00 [received]
PHST- 2013/02/18 00:00 [revised]
PHST- 2013/02/25 00:00 [accepted]
PHST- 2013/04/16 06:00 [entrez]
PHST- 2013/04/16 06:00 [pubmed]
PHST- 2014/01/21 06:00 [medline]
PHST- 2013/04/13 00:00 [pmc-release]
AID - CNS12098 [pii]
AID - 10.1111/cns.12098 [doi]
PST - ppublish
SO  - CNS Neurosci Ther. 2013 Jul;19(7):511-20. doi: 10.1111/cns.12098. Epub 2013 Apr 
      13.