Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signaling and cytokine expression by macrophages.

LRP1 is a type-1 transmembrane receptor that mediates the endocytosis of diverse ligands. LRP1 β-chain proteolysis results in release of sLRP1 that is present in human plasma. In this study, we show that LPS and IFN-γ induce shedding of LRP1 from RAW 264.

LIM kinase 1 promotes endothelial barrier disruption and neutrophil infiltration in mouse lungs.

Rationale: Disruption of endothelial barrier function and neutrophil-mediated injury are two major mechanisms underlying the pathophysiology of sepsis-induced acute lung injury (ALI). Recently we reported that endotoxin induced activation of RhoA in mice lungs that led to the disruption of endothelial barrier and lung edema formation; however, the molecular mechanism of this phenomenon remained unknown.

Objective: We reasoned that LIMK1, which participates in the regulation of endothelial cell contractility and is activated by RhoA/Rho kinase pathway, could mediate RhoA-dependent disruption of endothelial barrier function in mouse lungs during ALI.

Tiam1 and Rac1 are required for platelet-activating factor-induced endothelial junctional disassembly and increase in vascular permeability.

It is known that platelet-activating factor (PAF) induces severe endothelial barrier leakiness, but the signaling mechanisms remain unclear. Here, using a wide range of biochemical and morphological approaches applied in both mouse models and cultured endothelial cells, we addressed the mechanisms of PAF-induced disruption of interendothelial junctions (IEJs) and of increased endothelial permeability. The formation of interendothelial gaps filled with filopodia and lamellipodia is the cellular event responsible for the disruption of endothelial barrier.

Downregulation of LIM kinase 1 suppresses ocular inflammation and fibrosis.

Purpose: The purpose of this study was to determine if downregulation of LIM kinase 1 (LIMK1) by genetic deletion or direct application of LIMK1-targeted siRNA could suppress TGF-beta mediated ocular inflammation and fibrosis.

Methods: LIMK1 specific siRNAs designed from the human sequence were transfected into human corneal fibroblasts in culture. Immunofluorescence and immunoblotting were performed to examine the fibronectin assembly.

RhoGDI-1 modulation of the activity of monomeric RhoGTPase RhoA regulates endothelial barrier function in mouse lungs.

Rho family GTPases have been implicated in the regulation of endothelial permeability via their actions on actin cytoskeletal organization and integrity of interendothelial junctions. In cell culture studies, activation of RhoA disrupts interendothelial junctions and increases endothelial permeability, whereas activation of Rac1 and Cdc42 enhances endothelial barrier function by promoting the formation of restrictive junctions. The primary regulators of Rho proteins, guanine nucleotide dissociation inhibitors (GDIs), form a complex with the GDP-bound form of the Rho family of monomeric G proteins, and thus may serve as a nodal point regulating the activation state of RhoGTPases.

A novel mechanism of G protein-dependent phosphorylation of vasodilator-stimulated phosphoprotein.

Vasodilator-stimulated phosphoprotein (VASP) is a major substrate of protein kinase A (PKA). Here we described the novel mechanism of VASP phosphorylation via cAMP-independent PKA activation. We showed that in human umbilical vein endothelial cells (HUVECs) alpha-thrombin induced phosphorylation of VASP.

LIM kinase 1 coordinates microtubule stability and actin polymerization in human endothelial cells.

Microtubule (MT) destabilization promotes the formation of actin stress fibers and enhances the contractility of cells; however, the mechanism involved in the coordinated regulation of MTs and the actin cytoskeleton is poorly understood. LIM kinase 1 (LIMK1) regulates actin polymerization by phosphorylating the actin depolymerization factor, cofilin. Here we report that LIMK1 is also involved in the MT destabilization.