Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization

Glutaredoxin-1 (Glrx) is a cytosolic enzyme that regulates diverse cellular function by removal of GSH adducts from S-glutathionylated proteins including signaling molecules and transcription factors. Glrx is up-regulated during inflammation and diabetes. Glrx overexpression inhibits VEGF-induced endothelial cell (EC) migration. The aim was to investigate the role of up-regulated Glrx in EC angiogenic capacities and in vivo revascularization in the setting of hind limb ischemia. Glrx overexpressing EC from Glrx transgenic mice (TG) showed impaired migration and network formation and secreted higher level of soluble VEGF receptor 1 (sFlt), an antagonizing factor to VEGF. After hind limb ischemia surgery Glrx TG mice demonstrated impaired blood flow recovery, associated with lower capillary density and poorer limb motor function compared to wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Non-canonical Wnt5a is known to induce sFlt. Wnt5a was highly expressed in ischemic muscles and EC from Glrx TG mice, and exogenous Wnt5a induced sFlt expression and inhibited network formation in human microvascular EC. Adenoviral Glrx-induced sFlt in EC was inhibited by a competitive Wnt5a inhibitor. Furthermore, Glrx overexpression removed GSH adducts on p65 in ischemic muscle and EC, and enhanced nuclear factor kappa B (NF-kB) activity which was responsible for Wnt5a-sFlt induction. Taken together, up-regulated Glrx induces sFlt in EC via NF-kB -dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt may be a part of mechanism of redox regulated VEGF signaling.

Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1α and improve limb revascularization

Reactive oxygen species (ROS) are increased in ischemic tissues and necessary for revascularization; however, the mechanism remains unclear. Exposure of cysteine residues to ROS in the presence of glutathione (GSH) generates GSH-protein adducts that are specifically reversed by the cytosolic thioltransferase, glutaredoxin-1 (Glrx). Here, we show that a key angiogenic transcriptional factor hypoxia-inducible factor (HIF)-1α is stabilized by GSH adducts, and the genetic deletion of Glrx improves ischemic revascularization. In mouse muscle C2C12 cells, HIF-1α protein levels are increased by increasing GSH adducts with cell-permeable oxidized GSH (GSSG-ethyl ester) or 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanyl thiocarbonylamino) phenylthiocarbamoylsulfanyl] propionic acid (2-AAPA), an inhibitor of glutathione reductase. A biotin switch assay shows that GSSG-ester-induced HIF-1α contains reversibly modified thiols, and MS confirms GSH adducts on Cys520 (mouse Cys533). In addition, an HIF-1α Cys520 serine mutant is resistant to 2-AAPA–induced HIF-1α stabilization. Furthermore, Glrx overexpression prevents HIF-1α stabilization, whereas Glrx ablation by siRNA increases HIF-1α protein and expression of downstream angiogenic genes. Blood flow recovery after femoral artery ligation is significantly improved in Glrx KO mice, associated with increased levels of GSH-protein adducts, capillary density, vascular endothelial growth factor (VEGF)-A, and HIF-1α in the ischemic muscles. Therefore, Glrx ablation stabilizes HIF-1α by increasing GSH adducts on Cys520 promoting in vivo HIF-1α stabilization, VEGF-A production, and revascularization in the ischemic muscles

Adaptation of trailing spouses: Does gender matter?

The adaptation to a new country is a complex and stressful process that is compounded when changes in status and identity have to be made. This exploratory study examined the adaptation of international company transferee spouses when they decide to follow the transferee on overseas assignments. Research to date indicates that the spouses’ dissatisfaction with life abroad is the leading cause of transferees breaking contract and prematurely returning home. The causes of this dissatisfaction are still not clear and this study sought greater clarification, particularly examining the experiences of male as well as female trailing spouses. The study, thus, takes gender as a main variable to consider. It explores how gendered expectations inherent in the structures of society inflect and inform the decisions, attitudes, and behaviors that affect the adaptations of trailing spouses living in a foreign habitus. The study is based on eight months of ethnographic research in two culturally different locations, Kuala Lumpur, Malaysia and Brussels, Belgium. Forty-two American international company transferee spouses were recruited (seven males and thirty-five females). The data analysis revolved around five main themes: (1) the comparison of male with female trailing spouses’ experiences, (2) the effect of location on spouses’ adaptation, (3) the communities that spouses integrate into, (4) variations in personal work and family histories, and (5) conditions of exit. The analysis engaged multiple theories regarding gender, sociological adaptation, and psychological adaptation. Results indicate that both socio-cultural and psychological factors affect adaptation and that gender matters very significantly, particularly along two axes: (1) gendered structures in our society create different reasons why males and females become trailing spouses, (2) the gendered social constructions of role expectations make the experience of being a trailing husband different from being a trailing wife. In addition spouses’ status as parents (or not) and their “readiness for change” were found to be important predictors of positive spousal adaptation. In contrast, significant ties with families in the home country and strong professional identity with career projections were important predictors of negative spousal adaptation.

Adaptation of Trailing Spouses: Does Gender Matter?

The adaptation to a new country is a complex and stressful process that is compounded when changes in status and identity have to be made. This exploratory study examined the adaptation of international company transferee spouses when they decide to follow the transferee on overseas assignments. Research to date indicates that the spouses’ dissatisfaction with life abroad is the leading cause of transferees breaking contract and prematurely returning home. The causes of this dissatisfaction are still not clear and this study sought greater clarification, particularly examining the experiences of male as well as female trailing spouses. The study, thus, takes gender as a main variable to consider. It explores how gendered expectations inherent in the structures of society inflect and inform the decisions, attitudes, and behaviors that affect the adaptations of trailing spouses living in a foreign habitus. The study is based on eight months of ethnographic research in two culturally different locations, Kuala Lumpur, Malaysia and Brussels, Belgium. Forty-two American international company transferee spouses were recruited (seven males and thirty-five females). The data analysis revolved around five main themes: (1) the comparison of male with female trailing spouses’ experiences, (2) the effect of location on spouses’ adaptation, (3) the communities that spouses integrate into, (4) variations in personal work and family histories, and (5) conditions of exit. The analysis engaged multiple theories regarding gender, sociological adaptation, and psychological adaptation. Results indicate that both socio-cultural and psychological factors affect adaptation and that gender matters very significantly, particularly along two axes: (1) gendered structures in our society create different reasons why males and females become trailing spouses, (2) the gendered social constructions of role expectations make the experience of being a trailing husband different from being a trailing wife. In addition spouses’ status as parents (or not) and their “readiness for change” were found to be important predictors of positive spousal adaptation. In contrast, significant ties with families in the home country and strong professional identity with career projections were important predictors of negative spousal adaptation.

The role of supraspinal excitability in the development of healthy-limb deficits following anterior cruciate ligament injury

In the current study, we examined how supraspinal and spinal excitability were altered bilaterally after unilateral anterior cruciate ligament reconstruction (ACLr). 7 participants with ACLr and 7 healthy controls underwent transcranial magnetic stimulation (TMS) and electrical stimulation. To evaluate supraspinal excitability, resting motor thresholds (RMT) and motor evoked potential (MEP) stimulus response curves (SRC) were used. To measure spinal excitability, H-reflex SRC gain was assessed. Mixed factorial ANOVAs were used to compare measures between limbs and between groups. Cohen’s d was used to assess effect sizes between groups. Data indicated no significant differences between subject groups or between limbs. However, large effect sizes were found between limbs for H-reflex gain and RMTs suggesting that ACLr can have an effect on some of the variables examined. This study identified decreases in strength in the injured limbs and that subjects with an ACL injury exhibited decreases in spinal and supraspinal excitability of the quadriceps compared to Healthy controls.

Constructs of health belief and disabling distal upper limb pain

Peer reviewed