GLYCOGEN SYNTHASE KINASE-3β INHIBITORS PROTECT AGAINST THE ORGAN INJURY AND DYSFUNCTION CAUSED BY HEMORRHAGE AND RESUSCITATION

Abstract

Glycogen synthase kinase 3beta (GSK-3beta) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. Dysregulation of GSK-3beta has been implicated in the pathogenesis of several diseases including sepsis. Here we investigate the effects of 2 chemically distinct inhibitors of GSK-3beta, TDZD-8 and SB216763, on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock. Male Wistar rats were subjected to hemorrhage (sufficient to lower mean arterial blood pressure to 35 mmHg for 90 min) and subsequently resuscitated with shed blood for 4 h. Hemorrhage and resuscitation resulted in an increase in serum levels of (a) creatinine and, hence, renal dysfunction, and (b) alanine aminotransferase and aspartate aminotransferase and, hence, hepatic injury. Treatment of rats with either TDZD-8 (1 mg/kg, i.v.) or SB216763 (0.6 mg/kg, i.v.) 5 min before resuscitation abolished the renal dysfunction and liver injury caused by hemorrhagic shock. In addition, TDZD-8, but not SB216763, attenuated the increase caused by hemorrhage and resuscitation in plasma levels of the proinflammatory cytokine interleukin 6 and also of the anti-inflammatory cytokine interleukin 10. Neither of the GSK-3beta inhibitors however affected the delayed fall in blood pressure caused by hemorrhagic shock. Thus, we propose that inhibition of GSK-3beta may represent a novel therapeutic approach in the therapy of hemorrhagic shock.

Protection against Myocardial Ischemia/Reperfusion Injury in TLR4-Deficient Mice Is Mediated through a Phosphoinositide 3-Kinase-Dependent Mechanism

“…Phosphorylation of GSK-3␤ by Akt results in inactivation of the enzyme (35). Dugo et al (45,46) have reported that GSK-3␤ inhibition protects against organ injury and dysfunction in hemorrhagic shock and endotoxemia. We speculated that increased myocardial PI3K/Akt activity in TLR4 Ϫ/Ϫ mice might result in increased phosphorylation and inactivation of GSK-3␤.…”

TNF-induced activation of pulmonary microvessel endothelial cells: a role for GSK3β

“…In addition, phosphorylation of tyrosine in GSK3␣-Tyr279 and GSK3␤-Tyr216 promotes activity of GSK3␣/␤ (1,3,11,15,22,25). Importantly, GSK3␣/␤ activity is implicated in the cellular and organ response to a variety of inflammatory agents such as TNF␣ (9,25,31). ␤-catenin is constitutively phosphorylated by GSK3␣/␤ (1,3,22).…”

“…TNF␣ is a mediator of sepsis syndrome and acute respiratory distress syndrome (9,25,31). In pulmonary microvessel endothelial cells, this laboratory demonstrated TNF causes a PKC␣-mediated barrier dysfunction associated with dislocation of ␤-catenin from ␤-actin within the zonular adherence (10,12,18,23).…”

Glycogen Synthase Kinase-3 Facilitates Con A-Induced IFN-γ–Mediated Immune Hepatic Injury

“…One representative data set obtained from repeated experiments is shown. endotoxemic renal dysfunction, liver injury, pancreatic injury, and neuromuscular injury, most likely by downregulating inflammatory cell infiltration, cytokine production, and expression of iNOS and CD54 through NF-kB inactivation (46)(47)(48)(49). In this study, we demonstrated that GSK-3 facilitates IFN-g-mediated Jak2/STAT1 and NF-kB activation to regulate cytokine production 5 cells/24 well) were pretreated with TDZD-8 (10 mM) for 0.5 h and then treated with Con A (25 mg/ml) or PBS for 3 h. ELISA was used to determine the total production of IFN-g. Flow cytometric analysis of IFN-g expression in NKT cells was performed by three-color staining, and the changes of IFN-g expression are shown as the fold increase as compared with the normalized PBS-treated group.…”

“…GSK-3 is negatively regulated by serine phosphorylation, mainly through the PI3K/Akt pathways; in contrast, tyrosine phosphorylation positively regulates the catalytic activity of GSK-3 via a proline-rich tyrosine kinase 2-mediated pathway (33)(34)(35). The proapoptotic and proinflammatory properties of GSK-3 have also been demonstrated in various animal models of inflammation, including experimental lung injury, shock, spinal cord trauma, arthritis, ischemia/reperfusion injury, infection, asthma, colitis, renal failure, and hepatotoxicity (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50). GSK-3 is currently a known regulator of IFN-g signaling and is involved in IFN-g-induced inflammatory activation (51)(52)(53)(54)(55)(56)(57)(58)(59).…”