The lectin-like domain of TNF protects from listeriolysin-induced hyperpermeability in human pulmonary microvascular endothelial cells — A crucial role for protein kinase C-α inhibition

Xiong, Chenling; Yang, Guang; Kumar, Sanjiv; Aggarwal, Saurabh; Leustik, Martin; Snead, Connie; Hamacher, Juerg; Fischer, Bernhard; Umapathy, Nagavedi S.; Hossain, Hamid; Wendel, Albrecht; Catravas, John D.; Verin, Alexander D.; Fulton, David; Black, Stephen M.; Chakraborty, Trinad; Lucas, Rudolf

doi:10.1016/j.vph.2009.12.010

Cited by 25 publications

(31 citation statements)

References 36 publications

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“…6C). The ability of LLO to promote calcium entry results from actions on plasma membrane calcium channels [36]. To determine the importance of calcium entry to LLO stimulated endothelial barrier disruption, we employed a non-selective steric inhibitor of plasma membrane calcium-channels, lanthanum chloride (LaCl 3 ).…”

Section: Resultsmentioning

confidence: 99%

RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G + -bacterial toxins

Chen

Wang

Rafikov

et al. 2017

Biochemical Pharmacology

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Disruption of the endothelial barrier in response to Gram positive (G+) bacterial toxins is a major complication of acute lung injury (ALI) and can be further aggravated by antibiotics which stimulate toxin release. The integrity of the pulmonary endothelial barrier is mediated by the balance of disruptive forces such as the small GTPase RhoA, and protective forces including endothelium-derived nitric oxide (NO). How NO protects against the barrier dysfunction is incompletely understood and our goal was to determine whether NO and S-nitrosylation can modulate RhoA activity and whether this mechanism is important for G+ toxin-induced microvascular permeability. We found that the G+ toxin listeriolysin-O (LLO) increased RhoA activity and that NO and S-NO donors inhibit RhoA activity. RhoA was robustly S-nitrosylated as determined by biotin-switch and mercury column analysis. MS revealed that three primary cysteine residues are S-nitrosylated including cys16, cys20 and cys159. Mutation of these residues to serine diminished S-nitrosylation to endogenous NO and mutant RhoA was less sensitive to inhibition by S-NO. G+-toxins stimulated the denitrosylation of RhoA which was not mediated by S-nitrosoglutathione reductase (GSNOR), thioredoxin (TRX) or thiol-dependent enzyme activity but was instead stimulated directly by elevated calcium levels. Calcium-promoted the direct denitrosylation of WT but not mutant RhoA and mutant RhoA adenovirus was more effective than WT in disrupting the barrier integrity of human lung microvascular endothelial cells. In conclusion, we reveal a novel mechanism by which NO and S-nitrosylation reduces RhoA activity which may be of significance in the management of pulmonary endothelial permeability induced by G+-toxins.

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Section: Resultsmentioning

confidence: 99%

RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G + -bacterial toxins

Chen

Wang

Rafikov

et al. 2017

Biochemical Pharmacology

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“…Cytoplasmic hemolytic PLY is released during autolysis, such as occurs because of antibiotic treatment (7,8), and subsequently binds to cholesterol in cell membranes, upon which oligomerization and pore formation take place. These pores facilitate increased intracellular Ca 2+ levels (9), which in turn activate mechanisms leading to contraction of endothelial cells (10,11). These pathways include both myosin light chain (MLC)-dependent mechanisms and microtubule depolymerization, the latter of which can cause disassembly of adherens junction proteins, such as vascular endothelial (VE)-cadherin (12).…”

Section: Aggressive Treatment With Antibiotics In Patients Infected Withmentioning

confidence: 99%

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

Lucas

Sridhar

Rick

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na + transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na + /K + -ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na + uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema.pneumonia | cyclic AMP

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“…Others have demonstrated increased endothelial barrier dysfunction upon modulation of PKCα, PKCβ I , or PKCζ activities and/or expression (Ferro et al, 2000; Huang et al, 2005; Li et al, 2004; Nagpala et al, 1996). PKCα activation promoted endothelial barrier disruption in response to a variety of edemagenic agents, including α-thrombin, TNF-α, and ROS (Aschner et al, 1997; Ferro et al, 2000; Konstantoulaki et al, 2003; Sandoval et al, 2001; Xiong et al, 2010). Intriguingly, we have shown that activation of PKCδ is critical for maintenance of basal barrier function and attenuated agonist-induced increases in permeability (Figure 1) (Harrington et al, 2003; Harrington et al, 2005; Klinger et al, 2007); these functions correlated with enhanced focal adhesion formation, actin filament stabilization, and RhoA activation.…”

Section: Introductionmentioning

confidence: 99%

Interplay between FAK, PKCδ, and p190RhoGAP in the regulation of endothelial barrier function

Grinnell

Harrington

2012

Microvascular Research

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Disruption of either intercellular or extracellular junctions involved in maintaining endothelial barrier function can result in increased endothelial permeability. Increased endothelial permeability, in turn, allows for the unregulated movement of fluid and solutes out of the vasculature and into the surrounding connective tissue, contributing to a number of disease states, including stroke and pulmonary edema (Ermert et al., 1995; Lee and Slutsky, 2010; van Hinsbergh, 1997; Waller et al., 1996; Warboys et al., 2010). Thus, a better understanding of the molecular mechanisms by which endothelial cell junction integrity is controlled is necessary for development of therapies aimed at treating such conditions. In this review, we will discuss the functions of three signaling molecules known to be involved in regulation of endothelial permeability: focal adhesion kinase (FAK), protein kinase C delta (PKCδ), and p190RhoGAP (p190). We will discuss the independent functions of each protein, as well as the interplay that exists between them and the effects of such interactions on endothelial function.

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The lectin-like domain of TNF protects from listeriolysin-induced hyperpermeability in human pulmonary microvascular endothelial cells — A crucial role for protein kinase C-α inhibition

Cited by 25 publications

References 36 publications

RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G + -bacterial toxins

RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G + -bacterial toxins

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

Interplay between FAK, PKCδ, and p190RhoGAP in the regulation of endothelial barrier function

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