title: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Service of Endocrinology, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain; Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain; Department of Medicine, University of Valencia, Valencia, Spain. Electronic address: hernandez_antmij@gva.es.
authors: Antonio
authors: A
authors: Hernandez-Mijares
authors: Service of Endocrinology, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain; Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain.
authors: Celia
authors: C
authors: Bañuls
authors: Service of Endocrinology, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain; Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain.
authors: Susana
authors: S
authors: Rovira-Llopis
authors: Service of Endocrinology, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain.
authors: Noelia
authors: N
authors: Diaz-Morales
authors: Service of Endocrinology, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain.
authors: Irene
authors: I
authors: Escribano-Lopez
authors: Department of Pharmacology and CIBERehd, Faculty of Medicine, University of Valencia, Spain.
authors: Carmen
authors: C
authors: de Pablo
authors: Department of Pharmacology and CIBERehd, Faculty of Medicine, University of Valencia, Spain; Fundación General de Universidad de Valencia, Valencia, Spain.
authors: Angeles
authors: A
authors: Alvarez
authors: Service of Endocrinology, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain.
authors: Silvia
authors: S
authors: Veses
authors: Service of Endocrinology, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain; Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain. Electronic address: milagros.rocha@uv.es.
authors: Milagros
authors: M
authors: Rocha
authors: Service of Endocrinology, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain; Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain; Department of Physiology, University of Valencia, Valencia, Spain. Electronic address: Victor.Victor@uv.es.
authors: Victor M
authors: VM
authors: Victor
mesh_terms: D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002448:Cell Adhesion / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000097:blood; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood*; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D000069438:Ezetimibe / Q000627:therapeutic use*; D000069499:Ezetimibe, Simvastatin Drug Combination / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019821:Simvastatin / Q000627:therapeutic use*; D013030:Spain; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D000069499:Ezetimibe, Simvastatin Drug Combination; D002784:Cholesterol; D019821:Simvastatin; D000069438:Ezetimibe
keywords: Atherosclerosis; Ezetimibe; Hypercholesterolemia; Leukocyte/endothelium interaction; Mitochondria; Oxidative stress; Simvastatin