eprintid: 10118844 rev_number: 17 eprint_status: archive userid: 608 dir: disk0/10/11/88/44 datestamp: 2021-01-15 15:15:32 lastmod: 2021-10-20 23:30:31 status_changed: 2021-01-15 15:15:32 type: article metadata_visibility: show creators_name: Freitas, F creators_name: Tibiriçá, E creators_name: Singh, M creators_name: Fraser, PA creators_name: Mann, GE title: Redox Regulation of Microvascular Permeability: IL-1β Potentiation of Bradykinin-Induced Permeability Is Prevented by Simvastatin ispublished: pub divisions: UCL divisions: B02 divisions: C08 divisions: D09 divisions: G02 keywords: NADPH oxidase, bradykinin, interleukin 1β, microvascular permeability, reactive oxygen species, simvastatin note: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited abstract: Antioxidant effects of statins have been implicated in the reduction in microvascular permeability and edema formation in experimental and clinical studies. Bradykinin (Bk)-induced increases in microvascular permeability are potentiated by IL-1β; however, no studies have examined the protection afforded by statins against microvascular hyperpermeability. We investigated the effects of simvastatin pretreatment on albumin-fluorescein isothiocyanate conjugate (FITC-albumin) permeability in post-capillary venules in rat cremaster muscle. Inhibition of nitric oxide synthase with L-NAME (10µM) increased basal permeability to FITC-albumin, which was abrogated by superoxide dismutase and catalase. Histamine-induced (1 µM) permeability was blocked by L-NAME but unaffected by scavenging reactive oxygen species with superoxide dismutase (SOD) and catalase. In contrast, bradykinin-induced (1-100 nM) permeability increases were unaffected by L-NAME but abrogated by SOD and catalase. Acute superfusion of the cremaster muscle with IL-1β (30 pM, 10 min) resulted in a leftward shift of the bradykinin concentration-response curve. Potentiation by IL-1β of bradykinin-induced microvascular permeability was prevented by the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) inhibitor apocynin (1 µM). Pretreatment of rats with simvastatin (5 mg·kg-1, i.p.) 24 h before permeability measurements prevented the potentiation of bradykinin permeability responses by IL-1β, which was not reversed by inhibition of heme oxygenase-1 with tin protoporphyrin IX (SnPP). This study highlights a novel mechanism by which simvastatin prevents the potentiation of bradykinin-induced permeability by IL-1β, possibly by targeting the assembly of NADPH oxidase subunits. Our findings highlight the therapeutic potential of statins in the prevention and treatment of patients predisposed to inflammatory diseases. date: 2020-12-14 date_type: published official_url: http://dx.doi.org/10.3390/antiox9121269 oa_status: green full_text_type: pub pmcid: PMC7764912 language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1838978 doi: 10.3390/antiox9121269 pii: antiox9121269 publication_declined: 2021-02-24T23:28:02GMT lyricists_name: Santos Simoes De Freitas, Felipe lyricists_id: FSANT92 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Antioxidants volume: 9 number: 12 article_number: 1269 event_location: Switzerland citation: Freitas, F; Tibiriçá, E; Singh, M; Fraser, PA; Mann, GE; (2020) Redox Regulation of Microvascular Permeability: IL-1β Potentiation of Bradykinin-Induced Permeability Is Prevented by Simvastatin. Antioxidants , 9 (12) , Article 1269. 10.3390/antiox9121269 <https://doi.org/10.3390/antiox9121269>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10118844/1/antioxidants-09-01269.pdf