Effects of simvastatin, ezetimibe and simvastatin/ezetimibe on mitochondrial function and leukocyte/endothelial cell interactions in patients with hypercholesterolemia

Abstract

Background: Cholesterol-lowering therapy has been related with several beneficial effects; however, its influence on oxidative stress and endothelial function is not fully elucidated.

Aims: To investigate the effect of simvastatin and ezetimibe on mitochondrial function and leukocyte-endothelium interactions in polymorphonuclear cells of hyperlipidemic patients.

Methods: Thirty-nine hyperlipidemic patients were randomly assigned to one of two groups: one received simvastatin (40 mg/day) and the other received ezetimibe (10 mg/day) for 4 weeks, after which both groups were administered combined therapy for an additional 4-week period. Lipid profile, mitochondrial parameters (oxygen consumption, reactive oxygen species (ROS) and membrane potential), glutathione levels, superoxide dismutase activity, catalase activity and leukocyte/endothelial cell interactions and adhesion molecules -VCAM-1, ICAM-1, E-selectin, were evaluated.

Results: An improvement in lipid profile was observed after administration of simvastatin or ezetimibe alone (LDLc: -40.2 vs -19.6%, respectively), though this effect was stronger with the former (p < 0.001), and a further reduction was registered when the two were combined (LDLc: -50.7% vs -56.8%, respectively). In addition to this, simvastatin, ezetimibe and simvastatin + ezetimibe significantly increased oxygen consumption, membrane potential and glutathione content, and decreased levels of ROS, thereby improving mitochondrial function. Furthermore, simvastatin + ezetimibe increased catalase activity. In addition, simvastatin and simvastatin/ezetimibe improved leukocyte/endothelium interactions by decreasing leukocyte rolling and adhesion and increasing leukocyte rolling velocity. Finally, simvastatin, ezetimibe and simvastatin + ezetimibe reduced levels of the adhesion molecule ICAM-1, and ezetimibe + simvastatin significantly decreased levels of E-selectin.

Conclusion: Co-administration of simvastatin and ezetimibe has an additive cholesterol-lowering effect and beneficial consequences for mitochondrial function and leukocyte/endothelium interactions in leukocytes of hypercholesterolemic patients.

Keywords: Atherosclerosis; Ezetimibe; Hypercholesterolemia; Leukocyte/endothelium interaction; Mitochondria; Oxidative stress; Simvastatin.