FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2736703838> ?p ?o ?g. }

• W2736703838 abstract "Introduction Insulin-resistant type 2 diabetes mellitus (DM) leads to premature death and disability, primarily as a consequence of accelerated vascular disease. Shc homology 2-containing inositol 5 phosphatase-2 (SHIP2) is a lipid phosphatase that suppresses insulin signalling downstream of phosphoinositide-3-kinase (PI3K). Inhibition of SHIP2 has been proposed as a therapy for type II DM, but the potential impact on vascular function is currently undefined. Methods Mice with endothelium-specific deletion of the SHIP2 catalytic domain (ECSHIP2/+) were generated by crossing mice with LoxP sites flanking exons 18–19 of the Inppl gene with Tie2-Cre mice. Pulmonary endothelial cells (PECs) were isolated from lungs using anti-CD146 microbeads. SHIP2 knockdown was studied in human umbilical vein endothelial cells (HUVECs) by transducing with SHIP2 (or control) shRNA. Immunoblotting was performed in basal conditions and after insulin stimulation, using appropriate primary antibodies. Superoxide generation was quantified using dihydroethidium (DHE) fluorescence, and endothelial nitric oxide synthase (eNOS) activity via a 13C-l-arginine to 13C-l-citrulline conversion assay (quantified as% of baseline). Aortic hydrogen peroxide abundance was assessed using an Amplex Red assay. Vasomotor function was studied ex vivo in aortic rings. Statistical analysis was performed with unpaired and paired t-tests assuming unequal variance, with significance defined by p-values Results PECs derived from ECSHIP2Asâ€n/+ mice had increased basal and insulin-stimulated activation of downstream signalling intermediates, including pPDK1, S473 pAKT and S1177 peNOS. Nox2 protein expression was increased (1.19 fold; p=0.04), in association with increased superoxide abundance (2.20 fold; p=0.004). This was normalised both with the Nox2 specific inhibitor Gp91ds-tat (22% reduction; p=0.05) and PI3K inhibitors, Wortmannin (35% reduction; p=0.03) and LY294002 (26% reduction; p=0.03). SHIP2 transduction in HUVECs achieved~70% knockdown. Findings were recapitulated, with more abundant S473 pAKT and S1177 peNOS. Moreover, there was enhanced Nox2 expression (1.39 fold; p=0.41) and superoxide generation (1.42 fold; p=0.02), which was suppressed in the context of Nox2 (34% reduction; p=0.03) and PI3K inhibition (39% reduction; p=0.01 [Wortmannin], 13% reduction; p=0.05 [LY294002]). eNOS activity was reduced in ECSHIP2/+ PECs treated with insulin (114% [±6] vs 136% [±3]; p=0.01). Aortic rings from ECSHIP2/+ mice had blunted insulin-mediated vasodilation, increased hydrogen peroxide abundance, and impaired vasoconstriction in response to the non-selective NOS inhibitor L-NMMA (indicating reduced NO bioavailability). Conclusions Endothelial-specific SHIP2 inactivation causes PI3K- and Nox2-dependent oxidative stress and endothelial dysfunction. These data suggest that SHIP2 may not be an ideal therapeutic target for diabetes-associated vascular disease." @default.
• W2736703838 created "2017-07-31" @default.
• W2736703838 creator A5005835656 @default.
• W2736703838 creator A5020162501 @default.
• W2736703838 creator A5023624678 @default.
• W2736703838 creator A5025155035 @default.
• W2736703838 creator A5026755210 @default.
• W2736703838 creator A5042859346 @default.
• W2736703838 creator A5048070756 @default.
• W2736703838 creator A5053142558 @default.
• W2736703838 creator A5075170331 @default.
• W2736703838 creator A5077354357 @default.
• W2736703838 creator A5078715263 @default.
• W2736703838 creator A5079099986 @default.
• W2736703838 creator A5091491536 @default.
• W2736703838 date "2017-06-01" @default.
• W2736703838 modified "2023-10-05" @default.
• W2736703838 title "232 Endothelial ship2 knockout causes nox2 nadph oxidase-dependent oxidative stress and endothelial dysfunction" @default.
• W2736703838 doi "https://doi.org/10.1136/heartjnl-2017-311726.230" @default.
• W2736703838 hasPublicationYear "2017" @default.
• W2736703838 type Work @default.
• W2736703838 sameAs 2736703838 @default.
• W2736703838 citedByCount "0" @default.
• W2736703838 crossrefType "journal-article" @default.
• W2736703838 hasAuthorship W2736703838A5005835656 @default.
• W2736703838 hasAuthorship W2736703838A5020162501 @default.
• W2736703838 hasAuthorship W2736703838A5023624678 @default.
• W2736703838 hasAuthorship W2736703838A5025155035 @default.
• W2736703838 hasAuthorship W2736703838A5026755210 @default.
• W2736703838 hasAuthorship W2736703838A5042859346 @default.
• W2736703838 hasAuthorship W2736703838A5048070756 @default.
• W2736703838 hasAuthorship W2736703838A5053142558 @default.
• W2736703838 hasAuthorship W2736703838A5075170331 @default.
• W2736703838 hasAuthorship W2736703838A5077354357 @default.
• W2736703838 hasAuthorship W2736703838A5078715263 @default.
• W2736703838 hasAuthorship W2736703838A5079099986 @default.
• W2736703838 hasAuthorship W2736703838A5091491536 @default.
• W2736703838 hasBestOaLocation W27367038381 @default.
• W2736703838 hasConcept C126322002 @default.
• W2736703838 hasConcept C134018914 @default.
• W2736703838 hasConcept C181199279 @default.
• W2736703838 hasConcept C2776151105 @default.
• W2736703838 hasConcept C2776992346 @default.
• W2736703838 hasConcept C2779306644 @default.
• W2736703838 hasConcept C2779719074 @default.
• W2736703838 hasConcept C2780795997 @default.
• W2736703838 hasConcept C2780972559 @default.
• W2736703838 hasConcept C2781308076 @default.
• W2736703838 hasConcept C55493867 @default.
• W2736703838 hasConcept C71924100 @default.
• W2736703838 hasConcept C86803240 @default.
• W2736703838 hasConceptScore W2736703838C126322002 @default.
• W2736703838 hasConceptScore W2736703838C134018914 @default.
• W2736703838 hasConceptScore W2736703838C181199279 @default.
• W2736703838 hasConceptScore W2736703838C2776151105 @default.
• W2736703838 hasConceptScore W2736703838C2776992346 @default.
• W2736703838 hasConceptScore W2736703838C2779306644 @default.
• W2736703838 hasConceptScore W2736703838C2779719074 @default.
• W2736703838 hasConceptScore W2736703838C2780795997 @default.
• W2736703838 hasConceptScore W2736703838C2780972559 @default.
• W2736703838 hasConceptScore W2736703838C2781308076 @default.
• W2736703838 hasConceptScore W2736703838C55493867 @default.
• W2736703838 hasConceptScore W2736703838C71924100 @default.
• W2736703838 hasConceptScore W2736703838C86803240 @default.
• W2736703838 hasLocation W27367038381 @default.
• W2736703838 hasOpenAccess W2736703838 @default.
• W2736703838 hasPrimaryLocation W27367038381 @default.
• W2736703838 hasRelatedWork W1765582275 @default.
• W2736703838 hasRelatedWork W1815605230 @default.
• W2736703838 hasRelatedWork W2010902736 @default.
• W2736703838 hasRelatedWork W2058211067 @default.
• W2736703838 hasRelatedWork W2100998391 @default.
• W2736703838 hasRelatedWork W2127996877 @default.
• W2736703838 hasRelatedWork W2286662779 @default.
• W2736703838 hasRelatedWork W2341937107 @default.
• W2736703838 hasRelatedWork W2484838094 @default.
• W2736703838 hasRelatedWork W2590755538 @default.
• W2736703838 hasRelatedWork W2613070049 @default.
• W2736703838 hasRelatedWork W2736132555 @default.
• W2736703838 hasRelatedWork W2743716581 @default.
• W2736703838 hasRelatedWork W2895145626 @default.
• W2736703838 hasRelatedWork W2902823180 @default.
• W2736703838 hasRelatedWork W2971515898 @default.
• W2736703838 hasRelatedWork W3004992712 @default.
• W2736703838 hasRelatedWork W3091388376 @default.
• W2736703838 hasRelatedWork W974356212 @default.
• W2736703838 hasRelatedWork W2797185498 @default.
• W2736703838 isParatext "false" @default.
• W2736703838 isRetracted "false" @default.
• W2736703838 magId "2736703838" @default.
• W2736703838 workType "article" @default.