{"id":{"repo_id":"bradford","oai_identifier":"oai:bradscholars.brad.ac.uk:10454/19744.2"},"canonical_url":"https://search.dev.ndltd.org/etd/bradford/oai:bradscholars.brad.ac.uk:10454/19744.2","repository":{"repo_id":"bradford","name":"University of Bradford","base_url":"https://bradscholars.brad.ac.uk/oai/request"},"display":{"title":"Suppressor of cytokine signalling 3 (SOCS3) turnover and regulation of human saphenous vein smooth muscle cell signalling and function","abstract":"Neointimal hyperplasia (NIH) is a cardiovascular disease characterised by increased smooth muscle cell (SMC) inflammation and proliferation. Suppressor of cytokine signalling 3 (SOCS3) limits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways involved in vascular remodelling but is limited by its short biological half-life. Therefore, mutation of all 9 Lys residues that are potential sites of ubiquitylation to Arg should produce a mutated SOCS3 resistant to ubiquitin-mediated proteasomal degradation (“Lys-less” SOCS3). This study hypothesise that enhancing SOCS3 stability and limiting JAK/STAT signalling may provide sustained inhibition of the vascular remodelling in NIH. Lentiviral transduction of WT and Lys-less SOCS3 in human saphenous vein (HSVSMCs) was highly efficient after 48 hours (>97%) and was sustained over 2 weeks. Lys-less SOCS3 was resistant to ubiquitylation contrary to WT-transduced HSVECs, and Lys-less SOCS3 was more stable (t1/2=4h) than WT (t1/2<4h) (n=6, P<0.001) in HSVSMCs. In HSVSMCs, both Lys-less SOCS3 and WT inhibited sIL-6Rα/IL-6 mediated STAT3 activation but not extracellular signal regulated protein kinase 1/2 (ERK1/2) by 80±7% (Lys-lessSOCS3/pSTAT3) and 74±6% (WT/pSTAT3) (n=3, P<0.05) and similarly inhibited PDGF-mediated STAT3 activation but not ERK1/2 by 67±17% (Lys-less SOCS3/pSTAT3) and 72±18% (WT/pSTAT3) (n=3, P<0.05). Functionally, Lys-less SOCS3 and WT were equivalent in inhibiting sIL-6Rα/IL-6 and PDGF-induced proliferation, whilst having no effects on PDGF-induced migration in HSVSMCs. Lys-less SOCS3 can be successfully transduced into primary HSVSMCs. It is more stable than WT yet retains its functional ability to ameliorate pro-inflammatory signalling and SMC proliferation, making it an attractive option for developing treatment of NIH.","abstract_html":"Neointimal hyperplasia (NIH) is a cardiovascular disease characterised by increased smooth muscle cell (SMC) inflammation and proliferation. Suppressor of cytokine signalling 3 (SOCS3) limits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways involved in vascular remodelling but is limited by its short biological half-life. Therefore, mutation of all 9 Lys residues that are potential sites of ubiquitylation to Arg should produce a mutated SOCS3 resistant to ubiquitin-mediated proteasomal degradation (“Lys-less” SOCS3). This study hypothesise that enhancing SOCS3 stability and limiting JAK/STAT signalling may provide sustained inhibition of the vascular remodelling in NIH. Lentiviral transduction of WT and Lys-less SOCS3 in human saphenous vein (HSVSMCs) was highly efficient after 48 hours (&gt;97%) and was sustained over 2 weeks. Lys-less SOCS3 was resistant to ubiquitylation contrary to WT-transduced HSVECs, and Lys-less SOCS3 was more stable (t1/2=4h) than WT (t1/2&lt;4h) (n=6, P&lt;0.001) in HSVSMCs. In HSVSMCs, both Lys-less SOCS3 and WT inhibited sIL-6Rα/IL-6 mediated STAT3 activation but not extracellular signal regulated protein kinase 1/2 (ERK1/2) by 80±7% (Lys-lessSOCS3/pSTAT3) and 74±6% (WT/pSTAT3) (n=3, P&lt;0.05) and similarly inhibited PDGF-mediated STAT3 activation but not ERK1/2 by 67±17% (Lys-less SOCS3/pSTAT3) and 72±18% (WT/pSTAT3) (n=3, P&lt;0.05). Functionally, Lys-less SOCS3 and WT were equivalent in inhibiting sIL-6Rα/IL-6 and PDGF-induced proliferation, whilst having no effects on PDGF-induced migration in HSVSMCs. Lys-less SOCS3 can be successfully transduced into primary HSVSMCs. It is more stable than WT yet retains its functional ability to ameliorate pro-inflammatory signalling and SMC proliferation, making it an attractive option for developing treatment of NIH.","abstract_has_math":false,"creators":["Moshapa, Florah T."],"institution":"University of Bradford","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Palmer, Timothy M.","Riches-Suman, Kirsten","Elies, Jacobo"],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021","date_published":"2021","updated_at":"2026-07-24T01:13:22Z","subjects":["Neointimal hyperplasia (NIH)","Cytokine signalling 3 (SOCS3)","Janus kinase (JAK)","JAK/STAT signalling","Signal transducer and activator of transcription (STAT)","Human saphenous vein","Cell migration","Cell proliferation","Cardiovascular disease","Smooth muscle cell"],"languages":["en"],"rights":["<a rel=\"license\" href=\"http://creativecommons.org/licenses/by-nc-nd/3.0/\"><img alt=\"Creative Commons License\" style=\"border-width:0\" src=\"http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png\" /></a><br />The University of Bradford theses are licenced under a <a rel=\"license\" href=\"http://creativecommons.org/licenses/by-nc-nd/3.0/\">Creative Commons Licence</a>."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://bradscholars.brad.ac.uk/handle/10454/19744.2","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Palmer, Timothy M.","Riches-Suman, Kirsten","Elies, Jacobo"]},{"key":"dc:creator","label":"Author","values":["Moshapa, Florah T."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-03-31T14:55:18Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2024-01-02T13:49:38Z","2025-03-31T14:55:18Z"]},{"key":"dc:date.issued","label":"Date","values":["2021"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["School of Pharmacy and Medical Sciences. Faculty of Life Sciences"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Bradford"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Neointimal hyperplasia (NIH)","Cytokine signalling 3 (SOCS3)","Janus kinase (JAK)","JAK/STAT signalling","Signal transducer and activator of transcription (STAT)","Human saphenous vein","Cell migration","Cell proliferation","Cardiovascular disease","Smooth muscle cell"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["<a rel=\"license\" href=\"http://creativecommons.org/licenses/by-nc-nd/3.0/\"><img alt=\"Creative Commons License\" style=\"border-width:0\" src=\"http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png\" /></a><br />The University of Bradford theses are licenced under a <a rel=\"license\" href=\"http://creativecommons.org/licenses/by-nc-nd/3.0/\">Creative Commons Licence</a>."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://bradscholars.brad.ac.uk/handle/10454/19744.2"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Neointimal hyperplasia (NIH) is a cardiovascular disease characterised by increased smooth muscle cell (SMC) inflammation and proliferation. Suppressor of cytokine signalling 3 (SOCS3) limits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways involved in vascular remodelling but is limited by its short biological half-life. Therefore, mutation of all 9 Lys residues that are potential sites of ubiquitylation to Arg should produce a mutated SOCS3 resistant to ubiquitin-mediated proteasomal degradation (“Lys-less” SOCS3). This study hypothesise that enhancing SOCS3 stability and limiting JAK/STAT signalling may provide sustained inhibition of the vascular remodelling in NIH. Lentiviral transduction of WT and Lys-less SOCS3 in human saphenous vein (HSVSMCs) was highly efficient after 48 hours (>97%) and was sustained over 2 weeks. Lys-less SOCS3 was resistant to ubiquitylation contrary to WT-transduced HSVECs, and Lys-less SOCS3 was more stable (t1/2=4h) than WT (t1/2<4h) (n=6, P<0.001) in HSVSMCs. In HSVSMCs, both Lys-less SOCS3 and WT inhibited sIL-6Rα/IL-6 mediated STAT3 activation but not extracellular signal regulated protein kinase 1/2 (ERK1/2) by 80±7% (Lys-lessSOCS3/pSTAT3) and 74±6% (WT/pSTAT3) (n=3, P<0.05) and similarly inhibited PDGF-mediated STAT3 activation but not ERK1/2 by 67±17% (Lys-less SOCS3/pSTAT3) and 72±18% (WT/pSTAT3) (n=3, P<0.05). Functionally, Lys-less SOCS3 and WT were equivalent in inhibiting sIL-6Rα/IL-6 and PDGF-induced proliferation, whilst having no effects on PDGF-induced migration in HSVSMCs. Lys-less SOCS3 can be successfully transduced into primary HSVSMCs. It is more stable than WT yet retains its functional ability to ameliorate pro-inflammatory signalling and SMC proliferation, making it an attractive option for developing treatment of NIH."]},{"key":"dc:title","label":"Title","values":["Suppressor of cytokine signalling 3 (SOCS3) turnover and regulation of human saphenous vein smooth muscle cell signalling and function"]}]}],"canonical_facts":{"dc:contributor.advisor":["Palmer, Timothy M.","Riches-Suman, Kirsten","Elies, Jacobo"],"dc:creator":["Moshapa, Florah T."],"dc:date.accessioned":["2025-03-31T14:55:18Z"],"dc:date.available":["2024-01-02T13:49:38Z","2025-03-31T14:55:18Z"],"dc:date.issued":["2021"],"dc:description.abstract":["Neointimal hyperplasia (NIH) is a cardiovascular disease characterised by increased smooth muscle cell (SMC) inflammation and proliferation. Suppressor of cytokine signalling 3 (SOCS3) limits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways involved in vascular remodelling but is limited by its short biological half-life. Therefore, mutation of all 9 Lys residues that are potential sites of ubiquitylation to Arg should produce a mutated SOCS3 resistant to ubiquitin-mediated proteasomal degradation (“Lys-less” SOCS3). This study hypothesise that enhancing SOCS3 stability and limiting JAK/STAT signalling may provide sustained inhibition of the vascular remodelling in NIH. Lentiviral transduction of WT and Lys-less SOCS3 in human saphenous vein (HSVSMCs) was highly efficient after 48 hours (>97%) and was sustained over 2 weeks. Lys-less SOCS3 was resistant to ubiquitylation contrary to WT-transduced HSVECs, and Lys-less SOCS3 was more stable (t1/2=4h) than WT (t1/2<4h) (n=6, P<0.001) in HSVSMCs. In HSVSMCs, both Lys-less SOCS3 and WT inhibited sIL-6Rα/IL-6 mediated STAT3 activation but not extracellular signal regulated protein kinase 1/2 (ERK1/2) by 80±7% (Lys-lessSOCS3/pSTAT3) and 74±6% (WT/pSTAT3) (n=3, P<0.05) and similarly inhibited PDGF-mediated STAT3 activation but not ERK1/2 by 67±17% (Lys-less SOCS3/pSTAT3) and 72±18% (WT/pSTAT3) (n=3, P<0.05). Functionally, Lys-less SOCS3 and WT were equivalent in inhibiting sIL-6Rα/IL-6 and PDGF-induced proliferation, whilst having no effects on PDGF-induced migration in HSVSMCs. Lys-less SOCS3 can be successfully transduced into primary HSVSMCs. It is more stable than WT yet retains its functional ability to ameliorate pro-inflammatory signalling and SMC proliferation, making it an attractive option for developing treatment of NIH."],"dc:identifier.uri":["https://bradscholars.brad.ac.uk/handle/10454/19744.2"],"dc:language.iso":["en"],"dc:publisher.department":["School of Pharmacy and Medical Sciences. Faculty of Life Sciences"],"dc:publisher.institution":["University of Bradford"],"dc:rights":["<a rel=\"license\" href=\"http://creativecommons.org/licenses/by-nc-nd/3.0/\"><img alt=\"Creative Commons License\" style=\"border-width:0\" src=\"http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png\" /></a><br />The University of Bradford theses are licenced under a <a rel=\"license\" href=\"http://creativecommons.org/licenses/by-nc-nd/3.0/\">Creative Commons Licence</a>."],"dc:subject":["Neointimal hyperplasia (NIH)","Cytokine signalling 3 (SOCS3)","Janus kinase (JAK)","JAK/STAT signalling","Signal transducer and activator of transcription (STAT)","Human saphenous vein","Cell migration","Cell proliferation","Cardiovascular disease","Smooth muscle cell"],"dc:title":["Suppressor of cytokine signalling 3 (SOCS3) turnover and regulation of human saphenous vein smooth muscle cell signalling and function"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["PhD"]},"updated_at":"2026-07-24T01:13:22Z"}