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.
Highlights
Microvascular endothelial barrier disruption occurs in a large number of disease states, such as stroke, sepsis, diabetes, hereditary and acquired angioedema, commonly induced by a variety of endogenous inflammatory mediators such as bradykinin [1,2,3,4,5,6]
We previously reported that bradykinin-induced microvascular permeability in the brain pial microvasculature in vivo is directly associated with the release of reactive oxygen species following bradykinin receptor activation [20]
We investigate for the first time the effects of pretreatment of rats with simvastatin on bradykinin- and IL-1β-induced microvascular permeability using intravital microscopy in an intact cremaster muscle preparation that to date has not been reported
Summary
Microvascular endothelial barrier disruption occurs in a large number of disease states, such as stroke, sepsis, diabetes, hereditary and acquired angioedema, commonly induced by a variety of endogenous inflammatory mediators such as bradykinin [1,2,3,4,5,6]. Novel therapeutic approaches to prevent or reduce microvascular permeability are paramount to avoid tissue edema and to maintain sufficient blood supply to target organs. In this context, statins have been described to reduce vascular permeability and edema formation in different animal and clinical studies [7,8,9,10], yet the underlying mechanisms have not been investigated in an intact muscle microvasculature. Angiotensin converting enzyme 2 (ACE2) has been implicated as the cellular receptor of SARS-CoV-2 virus [15,16], and reduced ACE2 activity may indirectly activate the kallikrein–bradykinin pathway to increase vascular permeability [17]
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