Could pharmacological curtailment of the RhoA/Rho-kinase pathway reverse the endothelial barrier dysfunction associated with Ebola virus infection?

Eisa-Beygi, Shahram; Wen, Xiao‐Yan

doi:10.1016/j.antiviral.2014.12.005

Cited by 15 publications

(14 citation statements)

References 38 publications

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“…Since activation of the RhoA/ROCK pathway induces barrier dysfunction and increases permeability in various diseases 1 , 6 , 8 – 11 , there have been attempts to therapeutically inhibit the RhoA/ROCK pathway 37 , 72 , 73 . RVA-induced early dissociation of TJs was restored by the RhoA inhibitor CT04, the ROCK inhibitor Y27632, and the MLC inhibitor blebbistatin.…”

Section: Discussionmentioning

confidence: 99%

“…RVA-induced early dissociation of TJs was restored by the RhoA inhibitor CT04, the ROCK inhibitor Y27632, and the MLC inhibitor blebbistatin. Among therapeutic candidates aimed at inhibiting the RhoA/ROCK pathway, fasudil hydrochloride (HA-1077), a derivative of isoquinoline and the only clinically approved pharmacological inhibitor of ROCK, has been used for the treatment of cerebral vasospasm since 1995 37 , 72 – 74 . In addition, treatment with fasudil is effective in improving lipopolysaccharide (LPS)-induced endothelial barrier dysfunction and LPS-induced production of pro-inflammatory cytokines 75 – 78 .…”

Section: Discussionmentioning

confidence: 99%

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Rotavirus-Induced Early Activation of the RhoA/ROCK/MLC Signaling Pathway Mediates the Disruption of Tight Junctions in Polarized MDCK Cells

Soliman

Cho

Park

et al. 2018

Sci Rep

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Intestinal epithelial tight junctions (TJ) are a major barrier restricting the entry of various harmful factors including pathogens; however, they also represent an important entry portal for pathogens. Although the rotavirus-induced early disruption of TJ integrity and targeting of TJ proteins as coreceptors are well-defined, the precise molecular mechanisms involved remain unknown. In the present study, infection of polarized MDCK cells with the species A rotavirus (RVA) strains human DS-1 and bovine NCDV induced a redistribution of TJ proteins into the cytoplasm, a reversible decrease in transepithelial resistance, and an increase in paracellular permeability. RhoA/ROCK/MLC signaling was identified as activated at an early stage of infection, while inhibition of this pathway prevented the rotavirus-induced early disruption of TJ integrity and alteration of TJ protein distribution. Activation of pMYPT, PKC, or MLCK, which are known to participate in TJ dissociation, was not observed in MDCK cells infected with either rotavirus strain. Our data demonstrated that binding of RVA virions or cogent VP8* proteins to cellular receptors activates RhoA/ROCK/MLC signaling, which alters TJ protein distribution and disrupts TJ integrity via contraction of the perijunctional actomyosin ring, facilitating virion access to coreceptors and entry into cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rotavirus-Induced Early Activation of the RhoA/ROCK/MLC Signaling Pathway Mediates the Disruption of Tight Junctions in Polarized MDCK Cells

Soliman

Cho

Park

et al. 2018

Sci Rep

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“…The three primary readouts used (rescue of mortality, rescue of the tail phenotype and rescue of ROS production) are very straightforward and do not require invasive procedures. One of the leads identified by this screen was fasudil, an inhibitor of the RhoA/ Rho-kinase pathway, which has been implicated in loss of endothelial barrier function and increased vascular permeability associated with endotoxin-induced sepsis (53). Furthermore, fasudil has also been shown to rescue LPS-induced vascular leakage in mouse models (29).…”

Section: Disclosurementioning

confidence: 99%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

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Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug-development pipeline is time-consuming and expensive, and the low success rates associated with cell-based screens underline the need for whole-organism screening strategies, especially for complex pathological processes. Here, we established a lipopolysaccharide (LPS)-induced zebrafish endotoxemia model, which exhibits the major hallmarks of human sepsis, including edema and tissue/organ damage, increased vascular permeability and vascular leakage accompanied by altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and reactive oxygen species (ROS) production, reduced circulation and increased platelet aggregation. We tested the suitability of the model for phenotype-based drug screening using three primary readouts: mortality, vascular leakage and ROS production. Preliminary screening identified fasudil, a drug known to protect against vascular leakage in murine models, as a lead hit, thereby validating the utility of our model for sepsis drug screens. This zebrafish sepsis model has the potential to rapidly analyze sepsis-associated pathologies and cellular processes in the whole organism, as well as to screen and validate many compounds that can modify sepsis pathology in vivo.

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“…A second Leptospira -affected protein, the small GTPase RhoA, is an important molecule that regulates the assembly of the actin cytoskeleton and the remodeling of cell junction proteins. RhoA activity accompanied by actin remodeling can lead to a loss of endothelial barrier integrity [ 52 , 54 – 56 ]. In both endothelial cell types we tested, the fluorescence intensity of small GTPase RhoA was slightly elevated by Copenhageni (1.3- to 1.4-fold) and Patoc (1.1- to 1.2-fold) infection ( Fig 3B ).…”

Section: Resultsmentioning

confidence: 99%

“…To regulate the adherens junction organization and endothelial permeability, some small GTPases are involved [ 53 , 84 ]. For example, the small GTPase RhoA controls the endothelial barrier integrity via remodeling of the actin cytoskeleton and of junction proteins [ 52 , 54 – 56 ]. In this study, Leptospira infection altered the actin cytoskeleton along with a moderate elevation of the RhoA signal (Figs 6 and 3B ).…”

Section: Discussionmentioning

confidence: 99%

Leptospira interrogans causes quantitative and morphological disturbances in adherens junctions and other biological groups of proteins in human endothelial cells

Satō

Coburn

2017

PLoS Negl Trop Dis

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Pathogenic Leptospira transmits from animals to humans, causing the zoonotic life-threatening infection called leptospirosis. This infection is reported worldwide with higher risk in tropical regions. Symptoms of leptospirosis range from mild illness to severe illness such as liver damage, kidney failure, respiratory distress, meningitis, and fatal hemorrhagic disease. Invasive species of Leptospira rapidly disseminate to multiple tissues where this bacterium damages host endothelial cells, increasing vascular permeability. Despite the burden in humans and animals, the pathogenic mechanisms of Leptospira infection remain to be elucidated. The pathogenic leptospires adhere to endothelial cells and permeabilize endothelial barriers in vivo and in vitro. In this study, human endothelial cells were infected with the pathogenic L. interrogans serovar Copenhageni or the saprophyte L. biflexa serovar Patoc to investigate morphological changes and other distinctive phenotypes of host cell proteins by fluorescence microscopy. Among those analyzed, 17 proteins from five biological classes demonstrated distinctive phenotypes in morphology and/or signal intensity upon infection with Leptospira. The affected biological groups include: 1) extracellular matrix, 2) intercellular adhesion molecules and cell surface receptors, 3) intracellular proteins, 4) cell-cell junction proteins, and 5) a cytoskeletal protein. Infection with the pathogenic strain most profoundly disturbed the biological structures of adherens junctions (VE-cadherin and catenins) and actin filaments. Our data illuminate morphological disruptions and reduced signals of cell-cell junction proteins and filamentous actin in L. interrogans-infected endothelial cells. In addition, Leptospira infection, regardless of pathogenic status, influenced other host proteins belonging to multiple biological classes. Our data suggest that this zoonotic agent may damage endothelial cells via multiple cascades or pathways including endothelial barrier damage and inflammation, potentially leading to vascular hyperpermeability and severe illness in vivo. This work provides new insights into the pathophysiological mechanisms of Leptospira infection.

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Could pharmacological curtailment of the RhoA/Rho-kinase pathway reverse the endothelial barrier dysfunction associated with Ebola virus infection?

Cited by 15 publications

References 38 publications

Rotavirus-Induced Early Activation of the RhoA/ROCK/MLC Signaling Pathway Mediates the Disruption of Tight Junctions in Polarized MDCK Cells

Rotavirus-Induced Early Activation of the RhoA/ROCK/MLC Signaling Pathway Mediates the Disruption of Tight Junctions in Polarized MDCK Cells

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Leptospira interrogans causes quantitative and morphological disturbances in adherens junctions and other biological groups of proteins in human endothelial cells

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