RGD Reference Report - Sex differences in the response to poly(ADP-ribose) polymerase-1 deletion and caspase inhibition after stroke. - Rat Genome Database
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Sex differences in the response to poly(ADP-ribose) polymerase-1 deletion and caspase inhibition after stroke.

Authors: Liu, F  Lang, J  Li, J  Benashski, SE  Siegel, M  Xu, Y  McCullough, LD 
Citation: Liu F, etal., Stroke. 2011 Apr;42(4):1090-6. Epub 2011 Feb 10.
RGD ID: 5683909
Pubmed: (View Article at PubMed) PMID:21311064
DOI: Full-text: DOI:10.1161/STROKEAHA.110.594861

BACKGROUND AND PURPOSE: Emerging data suggest that the molecular cell death pathways triggered by ischemic insults differ in the male and female brain. Cell death in males is initiated by poly(ADP-ribose) polymerase-1 (PARP-1) activation; however, manipulation of this pathway paradoxically increases ischemic damage in females. In contrast, females are exquisitely sensitive to caspase-mediated cell death. The effect of caspase inhibition in PARP-1 knockout mice was evaluated to determine if the detrimental effects of PARP deletion in females were secondary to increased caspase activation. METHODS: Focal stroke was induced by transient or permanent middle cerebral artery occlusion (MCAO) in wild-type (WT) and PARP-1(-/-) mice of both sexes. The pan-caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh), was administered 90 minutes after middle cerebral artery occlusion. Infarct size and neurological sores were assessed. Separate cohorts were used for protein analysis for PAR, Apoptosis inducing factor (AIF), caspase-9, and caspase-3. RESULTS: WT mice of both sexes had increased nuclear AIF after stroke compared to PARP-1(-/-) mice. PARP-1(-/-) females had higher mitochondrial cytochrome C and activated caspase-9 and -3 levels than WT female mice. PARP-1(-/-) females also had an increase in stroke-induced cytosolic cytochrome C release compared with WT females, which was not seen in males. Q-VD-OPh decreased caspase-9 in both males and females but only led to reduction of infarct in females. PARP-1(-/-) males had smaller infarcts, whereas PARP-1(-/-) females had larger strokes compared with WT. Q-VD-OPh significantly decreased infarct in both WT and PARP-1(-/-) females in both transient and permanent MCAO models, but had no effect in males. CONCLUSIONS: Deletion of PARP-1 reduces infarct in males but exacerbates injury in females. PARP-1(-/-) females have enhanced caspase activation. The detrimental effects of PARP loss in females can be reversed with caspase inhibition.

Annotation

Disease Annotations    

Objects Annotated

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

Genes (Mus musculus)
Parp1  (poly (ADP-ribose) polymerase family, member 1)

Genes (Homo sapiens)
PARP1  (poly(ADP-ribose) polymerase 1)


Additional Information