Endothelial TAK1 Signaling and Resolution of Pulmonary Edema in Sepsis

University Of Illinois At Chicago, Chicago IL

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Sepsis associated with acute lung injury (ALI) is a common cause of death in hospitalized patients. ALI is in large part the result of lung vascular leakage and protein rich edema and there is a lack of effective therapy. Here, we have proposed a novel strategy to reverse ALI by stimulating an endogenous recovery process that is usually activated after lung injury. Thrombin, an edema-genic factor generated during sepsis, mediates pulmonary vascular leakage by activating protease-activated receptor-1 (PAR-1) on the endothelial cell surface. PAR-1-induced Ca2+ entry via store-operated Ca2+-entry channels (SOCs), disassembles endothelial adherens junctions (AJs) to cause increased lung vascular leak. An endoplasmic reticulum (ER) localized Ca2+ sensor protein stromal interacting molecule-1 (STIM1), is crucial for activating SOC to induce store- operated Ca2+-entry (SOCE) in endothelial cells (ECs). Now, we have identified in a murine model of tamoxifen-inducible endothelial cell (EC)-restricted TAK1 (Map3k7) deletion (Map3k7i?EC), a key role for TAK1 in resolving PAR-1-mediated pulmonary edema formation through regulation of the functions of STIM1, glycogen synthase kinase-3? (GSK-3?) and ?-catenin in ECs. We made the following observations (Supporting Data): i) TAK1 null ECs exhibited augmented SOCE and permeability in response to PAR-1 activation; ii) PAR-1-induced lung vascular permeability in vivo was not reversible in Map3k7i?EC mice; iii) ?- catenin expression was markedly reduced in ECs of Map3k7i?EC mice; iv) glycogen synthase kinase-3? (GSK- 3?) was persistently active in ECs of Map3k7i?EC mice, which may account for the markedly reduced expression of ?-catenin in ECs of Map3k7i?EC mice; v) PAR-1-medatied TAK1 activation was prevented in ECs of EC-restricted STIM1 knockout (Stim1?EC) mice; vi) surprisingly, we observed that SOCE signals the inactivation of GSK-3? via TAK1 activation in ECs; vii) importantly, PAR-1-mediated lung vascular leak was markedly reduced in tamoxifen-inducible EC-restricted GSK-3? knockout (GSK-3?i?EC) mice. Based on these novel observations, in Aim 1, we will test the hypothesis that TAK1 activation secondary to STIM1-mediated SOCE induces STIM1 phosphorylation which in turn inhibits SOCE and dampens lung vascular permeability. In Aim 2, we will test the hypothesis that TAK1 activation secondary to STIM1-mediated SOCE phosphorylates GSK-3? to inactivate GSK-3?, which in turn promotes increased ?-catenin expression at endothelial AJs to restore endothelial barrier integrity and thereby resolves pulmonary edema. A better understanding of the signaling mechanisms of TAK1 functions downstream of SOCE will lead to novel therapeutic approaches that will resolve pulmonary edema in sepsis.