Statins Prevent Dextrose-Induced Endothelial Barrier Dysfunction, Possibly Through Inhibition of Superoxide Formation

Abstract

Statins may have favorable effects on endothelial barrier function, possibly through reduction of oxidative stress and modulation of expression of vasoactive proteins. The permeability of human umbilical endothelial cells in culture to a group of fluorescein isothiocyanate dextrans of different molecular weights were studied under various experimental conditions. Superoxide anion production was measured with an ethidium bromide fluorescence method. Cellular endothelin 1 mRNA and endothelin 1 in culture media were measured with Northern blots and enzyme immunoassays, respectively. Rosuvastatin (10 nmol/l) normalized the 500 mg/dl dextrose-induced permeability changes. Superoxide anion production induced by 500 mg/dl dextrose was inhibited by therapeutic concentrations of rosuvastatin or simvastatin (10 nmol/l), whereas the increased levels of cellular endothelin 1 mRNA and endothelin 1 in culture media was inhibited by supratherapeutic concentrations of statins (> or =0.1 micromol/l). In conclusion, 1) endothelial cell barrier dysfunction occurs in cells treated with high concentrations of dextrose, 2) statin treatment of endothelial cells normalizes barrier permeability, and 3) the favorable effects of statins may be attributed to the inhibition of the dextrose-induced increase in superoxide anions, whereas inhibition of endothelin expression was observed only at supratherapeutic concentrations.

Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction

“…Hit molecules included steroids, nonsteroidal anti-inflammatory agents, microtubular agents, mitochondrial uncouplers, and antimetabolites. Statins, which previously have been shown to suppress hyperglycemic ROS production in endothelial cells (11,12), also inhibited ROS production in our experimental conditions; however, these effects also were associated with a suppression of cellular viability (Supplementary Fig. 1).…”

Hyperbaric oxygen treatment augments the efficacy of cilazapril and simvastatin regimens in an experimental nephrotic syndrome model

“…Their benefits are not simply related to the reduction of intraglomerular pressures [34,35], but also result from the interruption of angiotensin II/oxidant stress/ inflammatory response cycle [33,36]. We used simvastatin as an alternative regimen because of its significant antioxidant properties [37,38]. The meta-analysis of the former studies shows that statins reduce proteinuria and prevent the loss of kidney functions as well [39].…”

An Overview of the Extra-Lipid Effects of Rosuvastatin

“…31 Additionally, rosuvastatin attenuated the dextroseinduced permeability of human umbilical vein endothelial cells towards dextrans, possibly via a drug-induced decrease in the ROS production as well as in the endothelin-1 expression and production by these cells. 28 This evidence implies a potential protective effect of this statin against oxidative stress-active and vasoactive protein-mediated endothelial barrier dysfunction associated with the diabetes mellitus. 28…”

“…26 Rosuvastatin induces an increase in endothelial NO synthase (eNOS) expression and activity during the atherosclerotic process 27 and a decrease in the vascular production of ROS that could confer to NO-dependent endothelial function improvement. 22,28 This benefit may also be mediated by the 8-isoprostane production reducing effect of the drug. It has been suggested that 8-isoprostane levels correlate with asymmetric dimethylarginine (ADMA), an endothelial NO synthase (eNOS) inhibitor, levels.…”