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Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by
in vitro and in vivo ischemic brain injury
#MMPMID28724891
Yang XS
; Yi TL
; Zhang S
; Xu ZW
; Yu ZQ
; Sun HT
; Yang C
; Tu Y
; Cheng SX
Sci Rep
2017[Jul]; 7
(1
): 5818
PMID28724891
show ga
Necroptosis, a novel type of programmed cell death, is involved in stroke-induced
ischemic brain injury. Although studies have sought to explore the mechanisms of
necroptosis, its signaling pathway has not yet to be completely elucidated. Thus,
we used oxygen-glucose deprivation (OGD) and middle cerebral artery occlusion
(MCAO) models mimicking ischemic stroke (IS) conditions to investigate mechanisms
of necroptosis. We found that OGD and MCAO induced cell death, local brain
ischemia and neurological deficit, while zVAD-fmk (zVAD, an apoptotic inhibitor),
GSK'872 (a receptor interacting protein kinase-3 (RIP3) inhibitor), and combined
treatment alleviated cell death and ischemic brain injury. Moreover, OGD and MCAO
upregulated protein expression of the triggers of necroptosis: receptor
interacting protein kinase-1 (RIP1), RIP3 and mixed lineage kinase domain-like
protein (MLKL). The upregulation of these proteins was inhibited by GSK'872,
combination treatments and RIP3 siRNA but not zVAD treatment. Intriguingly,
hypoxia-inducible factor-1 alpha (HIF-1?), an important transcriptional factor
under hypoxic conditions, was upregulated by OGD and MCAO. Similar to their
inhibitory effects on aforementioned proteins upregulation, GSK'872, combination
treatments and RIP3 siRNA decreased HIF-1? protein level. These findings indicate
that necroptosis contributes to ischemic brain injury induced by OGD and MCAO and
implicate HIF-1?, RIP1, RIP3, and MLKL in necroptosis.
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