RGD Reference Report - Zinc promotes the death of hypoxic astrocytes by upregulating hypoxia-induced hypoxia-inducible factor-1alpha expression via poly(ADP-ribose) polymerase-1. - Rat Genome Database

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Zinc promotes the death of hypoxic astrocytes by upregulating hypoxia-induced hypoxia-inducible factor-1alpha expression via poly(ADP-ribose) polymerase-1.

Authors: Pan, R  Chen, C  Liu, WL  Liu, KJ 
Citation: Pan R, etal., CNS Neurosci Ther. 2013 Jul;19(7):511-20. doi: 10.1111/cns.12098. Epub 2013 Apr 13.
RGD ID: 10414068
Pubmed: PMID:23582235   (View Abstract at PubMed)
PMCID: PMC3681853   (View Article at PubMed Central)
DOI: DOI:10.1111/cns.12098   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to zinc ion  IEP 10414068 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Parp1  (poly (ADP-ribose) polymerase 1)


Additional Information