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TWEAK Receptor Deficiency Has Opposite Effects on Female and Male Mice Subjected to Neonatal Hypoxia-Ischemia.

ABSTRACT: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine member of the TNF family. TWEAK binds to its only known receptor, Fn14, enabling it to activate downstream signaling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signaling in neonatal hypoxia-ischemia (HI). We found that after neonatal HI, both TWEAK and Fn14 expression were increased to a greater extent in male compared with female mice. To assess the role of TWEAK signaling after HI, the size of the injury was measured in neonatal mice genetically deficient in Fn14 and compared with their wild-type and heterozygote littermates. A significant sex difference in the Fn14 knockout (KO) animals was observed. Fn14 gene KO was beneficial in females; conversely, reducing Fn14 expression exacerbated the brain injury in male mice. Our findings indicate that the TWEAK/Fn14 pathway is critical for development of hypoxic-ischemic brain injury in immature animals. However, as the responses are different in males and females, clinical implementation depends on development of sex-specific therapies.

SUBMITTER: Kichev A

PROVIDER: S-EPMC5906546 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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TWEAK Receptor Deficiency Has Opposite Effects on Female and Male Mice Subjected to Neonatal Hypoxia-Ischemia.

Kichev Anton A Baburamani Ana A AA Vontell Regina R Gressens Pierre P Burkly Linda L Thornton Claire C Hagberg Henrik H

Frontiers in neurology 20180412

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine member of the TNF family. TWEAK binds to its only known receptor, Fn14, enabling it to activate downstream signaling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signaling in neonatal hypoxia-ischemia (HI). We found that after neonatal HI, both TWEAK and Fn14 expression were increased to a greater extent in male compared with female mice. To asses ...[more]

PMID: 29706927

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Project description:BackgroundCardiovascular disease increases with age in both sexes. Treatment can require cardiac surgery, where the hearts are pre-treated with protective cardioplegic solution before ischemia and reperfusion (I/R). While endogenous estrogen is beneficial in I/R, whether testosterone is involved is uncertain and whether age modifies responses to I/R is unclear. We investigated sex- and age-specific differences in I/R injury in the hearts pre-treated with clinically relevant cardioplegic solution.MethodsThe hearts were isolated from young (6-9 months) and old (20-28 months) mice of both sexes and perfused (Langendorff) with Krebs-Henseleit buffer (15 min, 37 °C), followed by St. Thomas' two cardioplegia (6 min, 6-7 °C), global ischemia (90 min, 23-24 °C), and reperfusion (30 min, 37 °C). The hearts were perfused with triphenyltetrazolium chloride to quantify infarct area. Testosterone's role was investigated in gonadectomized (GDX, 6-9 months) male mice; serum testosterone and estradiol were measured with ELISA assays.ResultsLeft ventricular developed pressure (LVDP) recovered to 67.3 ± 7.4% in the old compared to 21.8 ± 9.2% in the young male hearts (p < 0.05). Similar results were seen for rates of pressure development (+dP/dt) and decay (-dP/dt). Infarct areas were smaller in the old male hearts (16.6 ± 1.6%) than in the younger hearts (55.8 ± 1.2%, p < 0.05). By contrast, the hearts from young and old females exhibited a similar post-ischemic functional recovery and no age-dependent difference in infarcts. There was a sex difference in the young group, where ventricular function (LVDP, +dP/dt, -dP/dt) recovered better and infarcts were smaller in females than males. Estradiol levels were highest in young females. Testosterone was high in young males but low in females and old males, which suggested beneficial effects of low testosterone. Indeed, the hearts from GDX males exhibited much better recovery of LVDP in reperfusion than that from intact males (values were 64.4 ± 7.5 % vs. 21.8 ± 9.2%; p < 0.05). The GDX hearts also had smaller infarcts than the hearts from intact males (p < 0.05).ConclusionsAlthough age had no effect on susceptibility to I/R injury after cardioplegic arrest in females, it actually protected against injury in older males. Our findings indicate that low testosterone may be protective against I/R injury following cardioplegic arrest in older males.

Project description:It is well-established that organizational effects of sex steroids during early development are fundamental for sex-typical displays of, for example, mating and aggressive behaviors in rodents and other species. Male and female brains are known to differ with respect to neuronal morphology in particular regions of the brain, including the number and size of neurons, and the density and length of dendrites in nuclei of hypothalamus and amygdala. The aim of the present study was to use global proteomics to identify proteins differentially expressed in hypothalamus/amygdala during early development (postnatal day 8) of male, female and conditional androgen receptor knockout (ARNesDel) male mice, lacking androgen receptors specifically in the brain. Furthermore, verification of selected sexually dimorphic proteins was performed using targeted proteomics.Our proteomic approach, iTRAQ, allowed us to investigate expression differences in the 2998 most abundantly expressed proteins in our dissected tissues. Approximately 170 proteins differed between the sexes, and 38 proteins between ARNesDel and control males (p < 0.05). In line with previous explorative studies of sexually dimorphic gene expression we mainly detected subtle protein expression differences (fold changes <1.3). The protein MARCKS (myristoylated alanine rich C kinase substrate), having the largest fold change of the proteins selected from the iTRAQ analyses and of known importance for synaptic transmission and dendritic branching, was confirmed by targeted proteomics as differentially expressed between the sexes.Overall, our results provide solid evidence that a large number of proteins show sex differences in their brain expression and could potentially be involved in brain sexual differentiation. Furthermore, our finding of a sexually dimorphic expression of MARCKS in the brain during development warrants further investigation on the involvement in sexual differentiation of this protein.

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TWEAK Receptor Deficiency Has Opposite Effects on Female and Male Mice Subjected to Neonatal Hypoxia-Ischemia.

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TWEAK Receptor Deficiency Has Opposite Effects on Female and Male Mice Subjected to Neonatal Hypoxia-Ischemia.

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