title: Direct demonstration of an antiinflammatory effect of simvastatin in subjects with the metabolic syndrome.
abstract: BACKGROUND
  Metabolic syndrome (MS) is characterized by low-grade inflammation and confers an increased risk for cardiovascular disease. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce cardiovascular events in MS patients. There is a paucity of data examining the effect of statins on inflammation in MS.
  
  
  OBJECTIVE
  We aimed to test the effect of simvastatin (40 mg/d) compared with placebo on biomarkers of inflammation [high-sensitivity C-reactive protein (hsCRP) and monocytic cytokines TNF, IL-6, and IL-1] in MS subjects.
  
  
  METHODS
  We conducted a randomized, double-blind, placebo-controlled study at the University of California, Davis, Medical Center.
  
  
  METHODS
  Participants were subjects with MS.
  
  
  METHODS
  Simvastatin (40 mg/d) or placebo was administered for 8 wk.
  
  
  RESULTS
  The hsCRP levels were assayed using a high-sensitivity immunoassay. Monocyte cytokines were assayed by ELISA after activation with lipopolysaccharide. Simvastatin therapy significantly decreased hsCRP levels in MS subjects compared with placebo (P < 0.0005) and resulted in a significant reduction in plasma and lipopolysaccharide-activated monocytic release of IL-6 and TNF (P < 0.025). Simvastatin therapy significantly decreased nuclear factor-kappaB and increased Akt activity in MS subjects compared with placebo. To gain mechanistic insights, human monocytes were pretreated with lovastatin with and without mevalonate or a phosphatidyl-3-kinase inhibitor or Rho kinase inhibitor. Lovastatin significantly decreased Rho kinase and nuclear factor-kappaB activity, significantly increased Akt activity, and resulted in decreased monocyte IL-6 levels; these effects were reversed with mevalonate and geranylgeranyl pyrophosphate, indicating direct effects of statins on protein prenylation.
  
  
  CONCLUSIONS
  Thus, we show a direct antiinflammatory effect of simvastatin therapy in MS. These findings could partly explain the benefit of statin therapy in these patients.
authors.affiliation: Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis, Medical Center and Veterans Affairs Medical Center, Sacramento, California 95817, USA.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Devaraj
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Ishwarlal
authors.initials: I
authors.lastname: Jialal
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000032:analysis; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy*; D008875:Middle Aged; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010919:Placebos; D019821:Simvastatin / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D015850:Interleukin-6; D016328:NF-kappa B; D010919:Placebos; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D019821:Simvastatin; D051058:Oncogene Protein v-akt