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

• Published in: Antioxidants 2020-12, Vol.9 (12), p.1269
• Main Authors: Freitas, Felipe, Tibiriçá, Eduardo, Singh, Mita, Fraser, Paul A, Mann, Giovanni E
• Format: Article
• Language: English
• Subjects: Albumin; Antioxidants; Bradykinin; Catalase; Coronary vessels; Coronaviruses; COVID-19; Diabetes; Edema; Fluorescein isothiocyanate; Heme; Heme oxygenase (decyclizing); Histamine; Inflammatory diseases; interleukin 1β; Ischemia; Laboratory animals; Membrane permeability; microvascular permeability; Microvasculature; NAD(P)H oxidase; NADPH oxidase; NADPH-diaphorase; NG-Nitroarginine methyl ester; Nitric oxide; Nitric-oxide synthase; Oxygenase; Permeability; Protoporphyrin; Protoporphyrin IX; Reactive oxygen species; Rodents; Sepsis; Severe acute respiratory syndrome coronavirus 2; simvastatin; Superoxide dismutase; Veins & arteries
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox9121269

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 , 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.