Simvastatin Inhibits Inflammatory Properties ofStaphylococcus aureusα-Toxin

Abstract

Background-Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuates Staphylococcus aureus ␣-toxin-induced increase in leukocyte-endothelial interactions during exotoxemia. Methods and Results-The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 g/kg) was administered 18 hours before the study. Activation of microcirculation was induced by bolus administration of 40 g/kg S aureus ␣-toxin. Exotoxemia resulted in a significant and time-dependent increase in leukocyte rolling, adherence, and transmigration of leukocytes as well as P-selectin expression on the intestinal vascular endothelium. Pretreatment with simvastatin significantly inhibited exotoxin-induced leukocyte rolling from 71Ϯ10 to 14Ϯ4.7 cells/min (PϽ0.01) and adherence from 14Ϯ3.5 to 0.4Ϯ0.2 cells (PϽ0.01). In addition, simvastatin pretreatment significantly inhibited transmigration of leukocytes from 10.5Ϯ1.2 to 4.2Ϯ0.9 (PϽ0.05) cells. Immunohistochemical detection of endothelial cell adhesion molecule P-selectin showed a 50% decrease in endothelial cell surface expression after simvastatin treatment. Furthermore, simvastatin treatment resulted in enhanced expression of endothelial cell NO synthase III in the intestinal microcirculation. Conclusions-These results demonstrate that simvastatin interferes with exotoxin-induced leukocyte-endothelial cell interactions, which may be relevant in various infectious diseases. Statin treatment may offer a new therapeutic strategy for these clinical conditions.

Statin‐inhibited endothelial permeability could be associated with its effect on PECAM‐1 in endothelial cells

“…In recent years, the pleiotropic effects of statins, including a wide variety of vascular effects such as inhibiting vascular inflammation, have been recognized [2][3][4][5]. The effects of statins, for example, upregulation of eNOS expression, have been attributed to the inhibition of Rho protein [6,7].…”

Pravastatin attenuates tourniquet-induced skeletal muscle ischemia reperfusion injury

“…However, it is believed that statins have anti-inflammatory properties independent of their cholesterol-lowering properties, and have indeed been shown to attenuate renal and cardiac injury in a number of models of ischemia reperfusion (Lefer et al 1999, Joyce et al 2001. Furthermore, statins have been shown to inhibit the generation of superoxide in activated neutrophils by reducing tyrosine phosphorylation, and to reduce endotoxin-induced leukocyte endothelial cell interactions (Kanno et al 1999, Pruefer et al 2002.…”

Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

“…Recently, statins have been shown to attenuate leukocyte-endothelial cell interactions at sites of inflammation. 10,11 A suggested mechanism for this effect is that simvastatin suppresses the expression of adhesion molecules on endothelium [12][13][14] through activation of endothelial nitric oxide synthase (eNOS). [12][13][14][15][16] Because ICAM-1-mediated leukocyte-endothelial cell interaction is an important step in the development of diabetic retinopathy, simvastatin should have beneficial effects in the prevention of diabetic retinopathy through suppression of ICAM-1-mediated leukocyte adhesion to vessel walls.…”

“…10,11 A suggested mechanism for this effect is that simvastatin suppresses the expression of adhesion molecules on endothelium [12][13][14] through activation of endothelial nitric oxide synthase (eNOS). [12][13][14][15][16] Because ICAM-1-mediated leukocyte-endothelial cell interaction is an important step in the development of diabetic retinopathy, simvastatin should have beneficial effects in the prevention of diabetic retinopathy through suppression of ICAM-1-mediated leukocyte adhesion to vessel walls. Although eNOS is an important mediator for ICAM-1 expression, 2,6,8,17,18 vascular endothelial growth factor (VEGF) is another mediator that up-regulates ICAM-1 expression on endothelial cells 8,19 -24 and is an important cytokine in the induction of diabetic retinopathy.…”