FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3207603428> ?p ?o ?g. }

• W3207603428 endingPage "S115" @default.
• W3207603428 startingPage "S114" @default.
• W3207603428 abstract "BACKGROUND Natural killer (NK) cell impairment is a feature of pulmonary arterial hypertension (PAH) and contributes to disease development in mouse models of NK cell deficiency (Ormiston et al, Circulation, 2012; Ratsep et al, AJP Lung, 2018). PAH is also strongly associated with mutations in BMPR2, the gene encoding the type-II bone morphogenetic protein receptor. Genetic and experimental evidence point to a loss of BMPR2 in the pulmonary endothelium as a critical contributor to disease development. However, the impact of endothelial BMPR2 loss on NK cell impairment in PAH remains unknown. METHODS AND RESULTS SiRNA-mediated silencing of BMPR2 in human pulmonary artery endothelial cells (HPAEC) significantly reduced the surface presentation and secretion of the α-type receptor for interleukin-15 (IL-15Rα), a major regulator of NK cell survival, proliferation and activity. Assessment of IL-15Rα transcriptional variants by RNA-Seq and glycosylation by immunoblotting demonstrated that this reduction was not due to changes in receptor transcription or processing. Treatment of HPAECs with the matrix metalloproteinase inhibitor Batimastat also ruled out a role for altered IL-15Rα cleavage with BMPR2 silencing. Instead, confocal microscopy identified impaired trafficking of IL-15Rα through the trans-Golgi-network (TGN) in BMPR2-silenced cells. To evaluate the effects of impaired IL-15 mediated signaling and NK cell loss on PAH development, NK cell-deficient Il15-/- rats and immune-competent Il15+/+ littermates were exposed to either the monocrotaline (MCT) or SUGEN/hypoxia models of experimental pulmonary hypertension. While both male and female Il15-/- rats developed more severe disease than their wildtype counterparts in the SUGEN/Hypoxia model, only male Il15-/- rats demonstrated this enhanced severity in the MCT model, which is the only one of the two models to reproduce the sex-based difference in disease severity that is observed in human PAH patients. Assessment of genes associated with sex hormone signaling and metabolism identified a potential increase in pulmonary Cyp1b1 expression (n=5-7, p=0.08) in male MCT-challenged Il15-/- rats relative to Il15+/+ controls. CONCLUSION We have identified the loss of IL-15 signaling as a novel BMPR2-dependent contributor to NK cell impairment and pulmonary arterial hypertension pathogenesis. Ongoing work includes assessing the contribution of sex hormones to immune-mediated disease processes in PAH. Natural killer (NK) cell impairment is a feature of pulmonary arterial hypertension (PAH) and contributes to disease development in mouse models of NK cell deficiency (Ormiston et al, Circulation, 2012; Ratsep et al, AJP Lung, 2018). PAH is also strongly associated with mutations in BMPR2, the gene encoding the type-II bone morphogenetic protein receptor. Genetic and experimental evidence point to a loss of BMPR2 in the pulmonary endothelium as a critical contributor to disease development. However, the impact of endothelial BMPR2 loss on NK cell impairment in PAH remains unknown. SiRNA-mediated silencing of BMPR2 in human pulmonary artery endothelial cells (HPAEC) significantly reduced the surface presentation and secretion of the α-type receptor for interleukin-15 (IL-15Rα), a major regulator of NK cell survival, proliferation and activity. Assessment of IL-15Rα transcriptional variants by RNA-Seq and glycosylation by immunoblotting demonstrated that this reduction was not due to changes in receptor transcription or processing. Treatment of HPAECs with the matrix metalloproteinase inhibitor Batimastat also ruled out a role for altered IL-15Rα cleavage with BMPR2 silencing. Instead, confocal microscopy identified impaired trafficking of IL-15Rα through the trans-Golgi-network (TGN) in BMPR2-silenced cells. To evaluate the effects of impaired IL-15 mediated signaling and NK cell loss on PAH development, NK cell-deficient Il15-/- rats and immune-competent Il15+/+ littermates were exposed to either the monocrotaline (MCT) or SUGEN/hypoxia models of experimental pulmonary hypertension. While both male and female Il15-/- rats developed more severe disease than their wildtype counterparts in the SUGEN/Hypoxia model, only male Il15-/- rats demonstrated this enhanced severity in the MCT model, which is the only one of the two models to reproduce the sex-based difference in disease severity that is observed in human PAH patients. Assessment of genes associated with sex hormone signaling and metabolism identified a potential increase in pulmonary Cyp1b1 expression (n=5-7, p=0.08) in male MCT-challenged Il15-/- rats relative to Il15+/+ controls. We have identified the loss of IL-15 signaling as a novel BMPR2-dependent contributor to NK cell impairment and pulmonary arterial hypertension pathogenesis. Ongoing work includes assessing the contribution of sex hormones to immune-mediated disease processes in PAH." @default.
• W3207603428 created "2021-10-25" @default.
• W3207603428 creator A5009125165 @default.
• W3207603428 creator A5018305754 @default.
• W3207603428 creator A5022097331 @default.
• W3207603428 creator A5031587045 @default.
• W3207603428 creator A5039050129 @default.
• W3207603428 creator A5047150414 @default.
• W3207603428 creator A5059343630 @default.
• W3207603428 creator A5067927464 @default.
• W3207603428 creator A5078106567 @default.
• W3207603428 creator A5082647977 @default.
• W3207603428 creator A5085844407 @default.
• W3207603428 date "2021-10-01" @default.
• W3207603428 modified "2023-09-27" @default.
• W3207603428 title "ENDOTHELIAL BMPR2 LOSS PROMOTES ALTERED IL-15 SIGNALING, CONTRIBUTING TO IMMUNE DYSFUNCTION IN PULMONARY HYPERTENSION" @default.
• W3207603428 doi "https://doi.org/10.1016/j.cjca.2021.07.217" @default.
• W3207603428 hasPublicationYear "2021" @default.
• W3207603428 type Work @default.
• W3207603428 sameAs 3207603428 @default.
• W3207603428 citedByCount "0" @default.
• W3207603428 crossrefType "journal-article" @default.
• W3207603428 hasAuthorship W3207603428A5009125165 @default.
• W3207603428 hasAuthorship W3207603428A5018305754 @default.
• W3207603428 hasAuthorship W3207603428A5022097331 @default.
• W3207603428 hasAuthorship W3207603428A5031587045 @default.
• W3207603428 hasAuthorship W3207603428A5039050129 @default.
• W3207603428 hasAuthorship W3207603428A5047150414 @default.
• W3207603428 hasAuthorship W3207603428A5059343630 @default.
• W3207603428 hasAuthorship W3207603428A5067927464 @default.
• W3207603428 hasAuthorship W3207603428A5078106567 @default.
• W3207603428 hasAuthorship W3207603428A5082647977 @default.
• W3207603428 hasAuthorship W3207603428A5085844407 @default.
• W3207603428 hasConcept C104317684 @default.
• W3207603428 hasConcept C119056186 @default.
• W3207603428 hasConcept C203014093 @default.
• W3207603428 hasConcept C2778690821 @default.
• W3207603428 hasConcept C31507581 @default.
• W3207603428 hasConcept C502942594 @default.
• W3207603428 hasConcept C55493867 @default.
• W3207603428 hasConcept C71924100 @default.
• W3207603428 hasConcept C73834784 @default.
• W3207603428 hasConcept C74172505 @default.
• W3207603428 hasConcept C86803240 @default.
• W3207603428 hasConcept C95444343 @default.
• W3207603428 hasConcept C98119934 @default.
• W3207603428 hasConceptScore W3207603428C104317684 @default.
• W3207603428 hasConceptScore W3207603428C119056186 @default.
• W3207603428 hasConceptScore W3207603428C203014093 @default.
• W3207603428 hasConceptScore W3207603428C2778690821 @default.
• W3207603428 hasConceptScore W3207603428C31507581 @default.
• W3207603428 hasConceptScore W3207603428C502942594 @default.
• W3207603428 hasConceptScore W3207603428C55493867 @default.
• W3207603428 hasConceptScore W3207603428C71924100 @default.
• W3207603428 hasConceptScore W3207603428C73834784 @default.
• W3207603428 hasConceptScore W3207603428C74172505 @default.
• W3207603428 hasConceptScore W3207603428C86803240 @default.
• W3207603428 hasConceptScore W3207603428C95444343 @default.
• W3207603428 hasConceptScore W3207603428C98119934 @default.
• W3207603428 hasIssue "10" @default.
• W3207603428 hasLocation W32076034281 @default.
• W3207603428 hasOpenAccess W3207603428 @default.
• W3207603428 hasPrimaryLocation W32076034281 @default.
• W3207603428 hasRelatedWork W1973423407 @default.
• W3207603428 hasRelatedWork W1995772731 @default.
• W3207603428 hasRelatedWork W2029987724 @default.
• W3207603428 hasRelatedWork W2417387999 @default.
• W3207603428 hasRelatedWork W3009320286 @default.
• W3207603428 hasRelatedWork W4200576167 @default.
• W3207603428 hasRelatedWork W4224232191 @default.
• W3207603428 hasRelatedWork W4248284651 @default.
• W3207603428 hasRelatedWork W4281552451 @default.
• W3207603428 hasRelatedWork W4319923850 @default.
• W3207603428 hasVolume "37" @default.
• W3207603428 isParatext "false" @default.
• W3207603428 isRetracted "false" @default.
• W3207603428 magId "3207603428" @default.
• W3207603428 workType "article" @default.