Sex differences in cell death

Li, Hong; Pin, Scott; Zeng, Zhiyuan; Wang, Michael M.; Andreasson, Katrin; McCullough, Louise D.

doi:10.1002/ana.20538

Cited by 108 publications

(93 citation statements)

References 23 publications

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“…Cell death after oxygen-glucose deprivation is less extensive in female astrocytes 3 and in hippocampal slices from females. 4 These findings suggest that sex-specific sensitivity to cerebral ischemia is partly a function of the sex of cells. However, hormonal influences should not be discounted in our understanding of post-IBI cell death and recovery.…”

mentioning

confidence: 93%

Gender and the injured brain

Herson

Hurn

2010

Progress in Brain Research

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mentioning

confidence: 93%

Gender and the injured brain

Herson

Hurn

2010

Progress in Brain Research

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“…10 In vitro experiments have also shown sex differences in ischemic sensitivity even in the absence of sex steroids in the medium. 11 These studies suggest that the differences in ischemic sensitivity may be innate. Since the sex chromosome complement is intrinsically different in males (XY) and females (XX), we hypothesized that this may contribute to sex differences.…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement

Manwani

Bentivegna

Benashski

et al. 2014

J Cereb Blood Flow Metab

106

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Epidemiologic studies have shown sex differences in ischemic stroke. The four core genotype (FCG) mouse model, in which the testes determining gene, Sry, has been moved from Y chromosome to an autosome, was used to dissociate the effects of sex hormones from sex chromosome in ischemic stroke outcome. Middle cerebral artery occlusion (MCAO) in gonad intact FCG mice revealed that gonadal males (XXM and XYM) had significantly higher infarct volumes as compared with gonadal females (XXF and XYF). Serum testosterone levels were equivalent in adult XXM and XYM, as was serum estrogen in XXF and XYF mice. To remove the effects of gonadal hormones, gonadectomized FCG mice were subjected to MCAO. Gonadectomy significantly increased infarct volumes in females, while no change was seen in gonadectomized males, indicating that estrogen loss increases ischemic sensitivity. Estradiol supplementation in gonadectomized FCG mice rescued this phenotype. Interestingly, FCG male mice were less sensitive to effects of hormones. This may be due to enhanced expression of the transgene Sry in brains of FCG male mice. Sex differences in ischemic stroke sensitivity appear to be shaped by organizational and activational effects of sex hormones, rather than sex chromosomal complement.

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“…In contrast, caspase inhibition reduced injury after middle cerebral artery occlusion (MCAO) in females but had minimal effects in males (7). Sex differences have also been well documented in neonatal and in vitro models (2,8,9), eliminating the possibility that these effects are secondary solely to activational effects of gonadal hormones (10,11).…”

mentioning

confidence: 99%

miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia

Siegel

Benashski

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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159

138

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It is increasingly recognized that the mechanisms underlying ischemic cell death are sexually dimorphic. Stroke-induced cell death in males is initiated by the mitochondrial release of apoptosis-inducing factor, resulting in caspase-independent cell death. In contrast, ischemic cell death in females is primarily triggered by mitochondrial cytochrome c release with subsequent caspase activation. Because X-linked inhibitor of apoptosis (XIAP) is the primary endogenous inhibitor of caspases, its regulation may play a unique role in the response to injury in females. XIAP mRNA levels were higher in females at baseline. Stroke induced a significant decrease in XIAP mRNA in females, whereas no changes were seen in the male brain. However, XIAP protein levels were decreased in both sexes after stroke. MicroRNAs (miRNAs) predominantly induce translational repression and are emerging as a major regulators of mRNA and subsequent protein expression after ischemia. The miRNA miR-23a was predicted to bind XIAP mRNA. miR-23a directly bound the 3′ UTR of XIAP, and miR-23a inhibition led to an increase in XIAP mRNA in vitro, demonstrating that XIAP is a previously uncharacterized target for miR-23a. miR-23a levels differed in male and female ischemic brains, providing evidence for sex-specific miRNA expression in stroke. Embelin, a small-molecule inhibitor of XIAP, decreased the interaction between XIAP and caspase-3 and led to enhanced caspase activity. Embelin treatment significantly exacerbated stroke-induced injury in females but had no effect in males, demonstrating that XIAP is an important mediator of sex-specific responses after stroke.middle cerebral artery occlusion | estrogen | ovariectomy | spectrin cleavage | second mitochondria-derived activator of caspases/direct inhibitor of apoptosis binding protein with low Pi

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Sex differences in cell death

Cited by 108 publications

References 23 publications

Gender and the injured brain

Gender and the injured brain

Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement

miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia

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