Heat Shock Protein 90 Inhibitors Prevent LPS-Induced Endothelial Barrier Dysfunction by Disrupting RhoA Signaling

Joshi, Atul; Dimitropoulou, Christiana; Thangjam, Gagan; Snead, Connie; Feldman, Sara; Barabutis, Nektarios; Fulton, David; Hou, Yali; Kumar, Sanjiv; Patel, Vijay; Gorshkov, Boris A; Verin, Alexander D.; Black, Stephen M.; Catravas, John D.

doi:10.1165/rcmb.2012-0496oc

Cited by 64 publications

(69 citation statements)

References 46 publications

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“…Both these agents have been previously observed in vitro to increase endothelial permeability (50)(51)(52). Conversely, in vivo studies using these agents causes varying results.…”

Section: Discussionmentioning

confidence: 99%

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

Chichger

Braza

Duong

et al. 2015

Am J Respir Cell Mol Biol

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Enhanced protein tyrosine phosphorylation is associated with changes in vascular permeability through formation and dissolution of adherens junctions and regulation of stress fiber formation. Inhibition of the protein tyrosine phosphorylase SH2 domaincontaining protein tyrosine phosphatase 2 (SHP2) increases tyrosine phosphorylation of vascular endothelial cadherin and b-catenin, resulting in disruption of the endothelial monolayer and edema formation in the pulmonary endothelium. Vascular permeability is a hallmark of acute lung injury (ALI); thus, enhanced SHP2 activity offers potential therapeutic value for the pulmonary vasculature in diseases such as ALI, but this has not been characterized. To assess whether SHP2 activity mediates protection against edema in the endothelium, we assessed the effect of molecular activation of SHP2 on lung endothelial barrier function in response to the edemagenic agents LPS and thrombin. Both LPS and thrombin reduced SHP2 activity, correlated with decreased focal adhesion kinase (FAK) phosphorylation (Y 397 and Y 925 ) and diminished SHP2 protein-protein associations with FAK. Overexpression of constitutively active SHP2 (SHP2 D61A ) enhanced baseline endothelial monolayer resistance and completely blocked LPSand thrombin-induced permeability in vitro and significantly blunted pulmonary edema formation induced by either endotoxin (LPS) or Pseudomonas aeruginosa exposure in vivo. Chemical inhibition of FAK decreased SHP2 protein-protein interactions with FAK concomitant with increased permeability; however, overexpression of SHP2 D61A rescued the endothelium and maintained FAK activity and FAK-SHP2 protein interactions. Our data suggest that SHP2 activation offers the pulmonary endothelium protection against barrier permeability mediators downstream of the FAK signaling pathway. We postulate that further studies into the promotion of SHP2 activation in the pulmonary endothelium may offer a therapeutic approach for patients suffering from ALI.Keywords: endothelium; SH2 domain-containing protein tyrosine phosphatase 2; pulmonary edema; acute lung injury; focal adhesion kinase Clinical RelevanceThis work studies the mechanism through which SHP2 activation protects the endothelial barrier against injury. In settings of acute lung injury, activation of SHP2 may offer a novel therapeutic approach to treat pulmonary edema.Acute respiratory distress syndrome (ARDS) is a complex syndrome associated with severe arterial hypoxemia. Onset of ARDS results from several predisposing factors, such as pneumonia, pancreatitis, sepsis, and trauma. At present, patients suffering from ARDS are treated with mechanical ventilation; however, there are insufficient treatment options available, and

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“…Both these agents have been previously observed in vitro to increase endothelial permeability (50)(51)(52). Conversely, in vivo studies using these agents causes varying results.…”

Section: Discussionmentioning

confidence: 99%

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

Chichger

Braza

Duong

et al. 2015

Am J Respir Cell Mol Biol

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show abstract

“…Western blot analyses and immunoprecipitation experiments were performed as described previously (9,31). Densitometry was performed using Image Studio version 3.1 from Licor and plotted as fold change from vehicle.…”

Section: Methodsmentioning

confidence: 99%

“…However, even short-term treatment (Ͻ4 h) with Hsp90 inhibitors attenuates LPS-induced RhoA activation and signaling and protects against LPS-mediated EBD in HLMVEC (31).…”

Section: Lps Potentiates Hsp90 Chaperone Function By Inducing Pp60mentioning

confidence: 97%

“…ROCK inhibitors block LPS-induced MLC phosphorylation and protect against LPSinduced EBD (23,37). Recently, we reported that Hsp90 inhibition attenuates LPS-induced RhoA activation and MLC phosphorylation in HLMVEC (31). Therefore, we hypothesized that HDAC inhibition would block the LPS-triggered and Hsp90-dependent RhoA-mediated signaling.…”

Section: Hdac Inhibition Protects Against the Lps-mediated Decrease Imentioning

confidence: 98%

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Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

Joshi

Barabutis

Birmpas

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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In this study we assessed the role of HDAC in mediating lipopolysaccharide (LPS)-induced transendothelial hyperpermeability and acute lung injury (ALI). We demonstrate that HDAC inhibition protects against LPS-mediated EBD. Inhibition of multiple HDAC by the general inhibitors panobinostat or trichostatin provided protection against LPS-induced transendothelial hyperpermeability, acetylated and suppressed Hsp90 chaperone function, and attenuated RhoA activity and signaling crucial to endothelial barrier function. Treatment with the HDAC3-selective inhibitor RGFP-966 or the HDAC6-selective inhibitor tubastatin A provided partial protection against LPS-mediated transendothelial hyperpermeability. Similarly, knock down of HDAC3 and HDAC6 by specific small-interfering RNAs provided significant protection against LPS-induced EBD. Furthermore, combined pharmacological inhibition of both HDAC3 and -6 attenuated the inflammation, capillary permeability, and structural abnormalities associated with LPS-induced ALI in mice. Together these data indicate that HDAC mediate increased transendothelial hyperpermeability caused by LPS and that inhibition of HDAC protects against LPS-mediated EBD and ALI by suppressing Hsp90-dependent RhoA activity and signaling.

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“…Birukokva and coworkers (15) showed that mechanical stretch in the phase of on-going endothelial barrier injury induces RhoA signaling via interleukin-6 receptors that otherwise induce Jak and p38 MAP kinase and NF-B signaling. NO, induced during pressure-induced shedding of glycocalyx by heparanase, is known to cause nitration of proteins including RhoA, which activates RhoA signaling (72,117). Thus a number of questions remain unanswered.…”

Section: Regulation Of Endothelial Barrier By Mechanical Stretchmentioning

confidence: 99%

Novel regulators of endothelial barrier function

Mehta

Ravindran

Kuebler

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

108

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Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial space, while allowing for the diffusive exchange of small molecules and the controlled trafficking of macromolecules and immune cells. Failure to control endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature that can rapidly become fatal in scenarios such as sepsis or the acute respiratory distress syndrome. Here, we highlight recent advances in our understanding on the regulation of endothelial permeability, with a specific focus on the endothelial glycocalyx and endothelial scaffolds, regulatory intracellular signaling cascades, as well as triggers and mediators that either disrupt or enhance endothelial barrier integrity, and provide our perspective as to areas of seeming controversy and knowledge gaps, respectively.

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Heat Shock Protein 90 Inhibitors Prevent LPS-Induced Endothelial Barrier Dysfunction by Disrupting RhoA Signaling

Cited by 64 publications

References 46 publications

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

Novel regulators of endothelial barrier function

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