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Article

Redox Regulation of Microvascular Permeability: IL-1β Potentiation of Bradykinin-Induced Permeability Is Prevented by Simvastatin

1
Centre of Research Excellence, King’s College London British Heart Foundation, School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King’s College London, 150 Stamford Street, London SE1 9NH, UK.
2
National Institute of Cardiology, Ministry of Health, Rio de Janeiro 22240-006, Brazil
*
Authors to whom correspondence should be addressed.
Present Address: Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, UK.
Antioxidants 2020, 9(12), 1269; https://doi.org/10.3390/antiox9121269
Received: 9 November 2020 / Revised: 8 December 2020 / Accepted: 9 December 2020 / Published: 14 December 2020
(This article belongs to the Special Issue Cellular Oxidative Stress)
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. View Full-Text
Keywords: microvascular permeability; bradykinin; interleukin 1β; NADPH oxidase; reactive oxygen species; simvastatin microvascular permeability; bradykinin; interleukin 1β; NADPH oxidase; reactive oxygen species; simvastatin
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MDPI and ACS Style

Freitas, F.; Tibiriçá, E.; Singh, M.; Fraser, P.A.; Mann, G.E. Redox Regulation of Microvascular Permeability: IL-1β Potentiation of Bradykinin-Induced Permeability Is Prevented by Simvastatin. Antioxidants 2020, 9, 1269. https://doi.org/10.3390/antiox9121269

AMA Style

Freitas F, Tibiriçá E, Singh M, Fraser PA, Mann GE. Redox Regulation of Microvascular Permeability: IL-1β Potentiation of Bradykinin-Induced Permeability Is Prevented by Simvastatin. Antioxidants. 2020; 9(12):1269. https://doi.org/10.3390/antiox9121269

Chicago/Turabian Style

Freitas, Felipe, Eduardo Tibiriçá, Mita Singh, Paul A. Fraser, and Giovanni E. Mann. 2020. "Redox Regulation of Microvascular Permeability: IL-1β Potentiation of Bradykinin-Induced Permeability Is Prevented by Simvastatin" Antioxidants 9, no. 12: 1269. https://doi.org/10.3390/antiox9121269

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