@article{discovery10118844,
           title = {Redox Regulation of Microvascular Permeability: IL-1{\ensuremath{\beta}} Potentiation of Bradykinin-Induced Permeability Is Prevented by Simvastatin},
         journal = {Antioxidants},
          volume = {9},
          number = {12},
            year = {2020},
           month = {December},
            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-1{\ensuremath{\beta}}; 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 (10uM) increased basal permeability to FITC-albumin, which was abrogated by superoxide dismutase and catalase. Histamine-induced (1 uM) 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-1{\ensuremath{\beta}} (30 pM, 10 min) resulted in a leftward shift of the bradykinin concentration-response curve. Potentiation by IL-1{\ensuremath{\beta}} of bradykinin-induced microvascular permeability was prevented by the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) inhibitor apocynin (1 uM). 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-1{\ensuremath{\beta}}, 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-1{\ensuremath{\beta}}, 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.},
          author = {Freitas, F and Tibiri{\cc}{\'a}, E and Singh, M and Fraser, PA and Mann, GE},
             url = {http://dx.doi.org/10.3390/antiox9121269},
        keywords = {NADPH oxidase, bradykinin, interleukin 1{\ensuremath{\beta}}, microvascular permeability, reactive oxygen species, simvastatin}
}