Abstract
endothelial cells (EC) dysfunction, thorough understanding of the statin effects on glucose uptake by these cells is of critical importance. Therefore, we investigated the influence of statins on glucose transport into EC and subsequently, we attempted to identify the mechanism of the observed effect. Methods: EC were incubated for 48 h with different concentrations of selected statins. Glucose transport into EC treated or not with insulin was assessed by incubation with H-2-deoxyglucose and dglucose fluorescent analogue, 6-NBDG and visualized using confocal microscopy. Lactate release was measured to assess the rate of glycolysis. Cytoskeletal F-actin organization was examined using TRITC-labeled phalloidin, whereas cellular fractions of free globular G-actin and filamentous F-actin were quantified by Western blot. Cholesterol and various intermediates of isoprenoid pathway: mevalonate (MVA), farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) were used to characterize the mechanism of statin-induced effect on glucose uptake. Results: All investigated statins decreased intracellular glucose transport and lactate release in the concentration-dependent manner. This suppressive effect was abolished by MVA and GGPP but not by FPP or cholesterol. Fluorescent staining of F-actin microfilaments showed disruption of actin cytoskeleton. This was further confirmed byWestern blot analysis, which revealed increased amount of G-actin and decreased F-actin in EC treated with statins. Conclusions: Our results indicate that the inhibitory effect of statins on both basal and insulin-induced glucose uptake is mediated by attenuation of cellular levels of GGPP. The rate of glycolysis, the major energy source in EC, is also reduced. We suggest that statins, by blocking the geranylgeranylation of GTP-binding proteins that are involved in cytoskeletal architecture and remodeling, disorganize actin cytoskeleton, impair the translocation of GLUTs (glucose transporters), and thus decrease glucose uptake. Our data may help to understand the development of diabetes type II in some patients treated with statins.
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