Endothelial STAT3 Activation Increases Vascular Leakage Through Downregulating Tight Junction Proteins: Implications for Diabetic Retinopathy

Yun, Jeong‐Ho; Park, Sung Wook; Kim, Kyung Jin; Bae, Jong Sup; Lee, Eun Hui; Paek, Sun Ha; Kim, Seung Up; Ye, Sang‐Kyu; Kim, Jeong Hun; Cho, Chung Hyun

doi:10.1002/jcp.25575

Cited by 103 publications

(87 citation statements)

References 45 publications

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“…Our results also showed that miR-15a/16 reduced endothelial cell permeability through downregulation of VEGF in REC under high glucose conditions. Inductive roles of VEGF on endothelial permeability have been reported in previous studies (Fischer et al, 1999; Qin et al, 2016; Yun et al, 2016). …”

Section: Discussionsupporting

confidence: 74%

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miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins

Liu

Steinle

2017

Vision Research

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Hyperglycemia is a significant risk factor for diabetic retinopathy and induces multiple biochemical changes, including inflammation and endothelial dysfunction in the retina. Alterations in microRNA expression have been implicated in the pathological responses of diabetic retinopathy and the manipulation of microRNA may provide powerful strategy for therapeutics. Among the predicted targets of miR-15a and -16 are TGF-beta3, SMAD2/3, and VEGF, all of which are known to play a role in vascular endothelial functions. The purpose of this study was to investigate the hypothesis that miR-15a/16 inhibits TGF-beta3/VEGF signaling to maintain retinal endothelial cell barrier protein levels. Human primary retinal endothelial cells (REC) were maintained in normal (5 mM) glucose or transferred to high glucose medium (25 mM) for 3 days. REC were transfected with miRNA mimics (hsa-miR-15a-5p and -16-5p). Retinal lysates from miR-15a-transgenic mice were also analyzed. We demonstrated that overexpression of miR-15a/16 resulted in decreased TGF-beta3 signaling and VEGF levels in cultured REC grown in high glucose conditions. In addition, the levels of tight junction proteins, zonula occludens-1 (ZO-1) and occludin, were elevated in REC following overexpression of miR-15a and -16. Overexpression of miR-15a and - 16 played a role in reducing cellular permeability through inhibition of VEGF signaling in REC cultured under high glucose conditions. Using miR-15a-transgenic mice, we demonstrated the regulatory role of miR-15a on TGF-beta3 signaling and tight junction proteins in vivo. Our outcomes suggest that miR-15a/16 maintain the retinal endothelial cell barrier by reducing TGFbeta3/VEGF signaling and increasing levels of key tight junction proteins.

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Section: Discussionsupporting

confidence: 74%

“…Additionally, it has been shown that VEGF increases endothelial permeability in retinal endothelial cells (Behzadian et al, 2003; Qin et al, 2016; Yun et al, 2016). Our recent study has shown an inhibitory role of miR-15a/16 on the inflammatory signaling of IL-1β, TNFα, NF-κB, as well as retinal leukostasis in vivo (Ye et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins

Liu

Steinle

2017

Vision Research

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“…Multivariate analyses from human patients also reveal a positive association between the presence of pneumonitis and the occurrence of scrub typhus meningitis and meningoencephalitis [47]. At present, it remains unclear how these lung responses influence neuroinflammation, but it has been shown that cytokine-mediated STAT3 activation can down-regulate occludin levels and increase endothelial permeability through the induction of VEGF production in EC [48]. Therefore, it will be important to further examine the molecular mechanisms underlying lung-brain infection and tissue damage and how such changes impact the release of proinflammatory cytokines and endogenous danger signals.…”

Section: Discussionmentioning

confidence: 99%

Type 1-skewed neuroinflammation and vascular damage associated with Orientia tsutsugamushi infection in mice

et al. 2017

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BackgroundScrub typhus is a life-threatening disease, due to infection with O. tsutsugamushi, a Gram-negative bacterium that preferentially replicates in endothelial cells and professional phagocytes. Meningoencephalitis has been reported in scrub typhus patients and experimentally-infected animals; however, the neurological manifestation and its underlying mechanisms remain poorly understood. To address this issue, we focused on Orientia tsutsugamushi Karp strain (OtK), and examined host responses in the brain during lethal versus self-healing scrub typhus disease in our newly established murine models.Principle findingsFollowing inoculation with a lethal dose of OtK, mice had a significant increase in brain transcripts related to pathogen-pattern recognition receptors (TLR2, TLR4, TLR9), type-1 responses (IFN-γ, TNF-α, CXCL9, CXCR3), and endothelial stress/damage such as angiopoietins, but a rapid down-regulation of Tie2. Sublethal infection displayed similar trends, implying the development of type 1-skewed proinflammatory responses in infected brains, independent of time and disease outcomes. Focal hemorrhagic lesions and meningitis were evident in both infection groups, but pathological changes were more diffuse and frequent in lethal infection. At 6–10 days of lethal infection, the cortex and cerebellum sections had increased ICAM-1-positive staining in vascular cells, as well as increased detection of CD45+ leukocytes, CD3+ T cells, IBA1+ phagocytes, and GFAP+ astrocytes, but a marked loss of occludin-positive tight junction staining, implying progressive endothelial activation/damage and cellular recruitment in inflamed brains. Orientia were sparse in the brains, but readily detectable within lectin+ vascular and IBA-1+ phagocytic cells. These CNS alterations were consistent with type 1-skewed, IL-13-suppressed responses in lethally-infected mouse lungs.SignificanceThis is the first report of type 1-skewed neuroinflammation and cellular activation, accompanied with vascular activation/damage, during OtK infection in C57BL/6 mice. This study not only enhances our understanding of the pathophysiological mechanisms of scrub typhus, but also correlates the impact of immune and vascular dysfunction on disease pathogenesis.

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“…STAT3 factors influence endothelial function in DR [34,35]. Thus, we focused on the relationship between O-GlcNAcylation and STAT3 phosphorylation, and changes to specific STAT3 sites under different O-GlcNAcylation levels.…”

Section: Discussionmentioning

confidence: 99%

“…STAT3 activation is also one of the main facilitators of BRB breakdown through increased VEGF expression [24] and downregulation of endothelial tight junction protein expression [25]. STAT3 proteins are targets of phosphorylation [24] focused on the sites of Tyr705 and Ser727 [26].…”

Section: Introductionmentioning

confidence: 99%

Identification of O-GlcNAcylation Modification in Diabetic Retinopathy and Crosstalk with Phosphorylation of STAT3 in Retina Vascular Endothelium Cells

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Recently, we observed an increase in O-GlcNAc (O-linked-ß-N-acetylglucosamine) modification, and signal transducer and activator of transcription proteins 3 (STAT3) expression in primary retinal vascular endothelial cells (RVECs) under high glucose conditions and tissues altered by diabetic retinopathy (DR). In this study, we focused on the correlations between O-GlcNAcylation and STAT3 phosphorylation, and their potential effects with regards to DR. Methods: Expression of O-GlcNAcylation and STAT3 were detected in DR-affected tissues and primary RVECs. The relationship between O-GlcNAcylation and STAT3 was further delineated by immunoprecipitation and Western blot analysis. Effects of O-GlcNAcylation on human RVEC apoptosis and involved protein expression were assayed with flow cytometry and Western blot. Results: Global O-GlcNAcylation and pSTAT3 levels were significantly elevated in diabetic rat retina and primary RVECs under high glucose conditions. In vitro assays demonstrated that the Tyr705 site was sensitive to high glucose. While O-GlcNAcylation inhibited p727STAT3 expression, augmented O-GlcNAcylation could balance p705STAT3 expression within relatively high levels corresponding to vascular endothelial growth factor (VEGF) changes. Immunoprecipitation revealed that STAT3 was modified by O-GlcNAcylation and phosphorylation simultaneously. Next, we observed that overexpression of O-GlcNAcylation could relieve human RVEC apoptosis related to the JAK2-Tyr705STAT3-VEGF pathway. Conclusion: O-GlcNAcylation could relieve RVECs apoptosis through the STAT3 pathway in DR, and O-GlcNAcylation combined with STAT3 phosphorylation might open up new insights into the mechanisms of DR and other diabetic complications.

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Endothelial STAT3 Activation Increases Vascular Leakage Through Downregulating Tight Junction Proteins: Implications for Diabetic Retinopathy

Cited by 103 publications

References 45 publications

miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins

miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins

Type 1-skewed neuroinflammation and vascular damage associated with Orientia tsutsugamushi infection in mice

Identification of O-GlcNAcylation Modification in Diabetic Retinopathy and Crosstalk with Phosphorylation of STAT3 in Retina Vascular Endothelium Cells

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