ArticleEBioMedicine2019
Inactivation of the tyrosine phosphatase SHP-2 drives vascular dysfunction in Sepsis.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 29 citations in OpenAlex.
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- Cx43 Promotes Endothelial Cell Migration and Angiogenesis via the Tyrosine Phosphatase SHP-2.International journal of molecular sciences · 2021Article
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- microRNA-193-3p attenuates myocardial injury of mice with sepsis via STAT3/HMGB1 axis.Journal of translational medicine · 2021Article
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- Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Promotes Inflammation and Accelerates Osteoarthritis by Activating β-Catenin.Frontiers in cell and developmental biology · 2021Article
- Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Leukocyte immunoglobulin-like receptor B4 protects against cardiac hypertrophy via SHP-2-dependent inhibition of the NF-κB pathway.Journal of molecular medicine (Berlin, Germany) · 2020Article
- TLR2-Deficiency Promotes Prenatal LPS Exposure-Induced Offspring Hyperlipidemia.Frontiers in physiology · 2019Article
- BUN and mortality in patients with heparin-induced thrombocytopenia: A retrospective cohort study.Science progressArticle
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Authors and funding
19 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundSepsis, the most severe form of infection, involves endothelial dysfunction which contributes to organ failure. To improve therapeutic prospects, elucidation of molecular mechanisms underlying endothelial vascular failure is of essence.
methodsPolymicrobial contamination induced sepsis mouse model and primary endothelial cells incubated with sepsis serum were used to study SHP-2 in sepsis-induced endothelial inflammation. SHP-2 activity was assessed by dephosphorylation of pNPP, ROS production was measured by DCF oxidation and protein interactions were assessed by proximity ligation assay. Vascular inflammation was studied in the mouse cremaster model and in an in vitro flow assay.
findingsWe identified ROS-dependent inactivation of the tyrosine phosphatase SHP-2 to be decisive for endothelial activation in sepsis. Using in vivo and in vitro sepsis models, we observed a significant reduction of endothelial SHP-2 activity, accompanied by enhanced adhesion molecule expression. The impaired SHP-2 activity was restored by ROS inhibitors and an IL-1 receptor antagonist. SHP-2 activity inversely correlated with the adhesive phenotype of endothelial cells exposed to IL-1β as well as sepsis serum via p38 MAPK and NF-κB. In vivo, SHP-2 inhibition accelerated IL-1β-induced leukocyte adhesion, extravasation and vascular permeability. Mechanistically, SHP-2 directly interacts with the IL-1R1 adaptor protein MyD88 via its tyrosine 257, resulting in reduced binding of p85/PI3-K to MyD88.
interpretationOur data show that SHP-2 inactivation by ROS in sepsis releases a protective break, resulting in endothelial activation. FUND: German Research Foundation, LMU Mentoring excellence and FöFoLe Programme, Verein zur Förderung von Wissenschaft und Forschung, German Ministry of Education and Research.
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