title: Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice: a clue to the disputed effect of statins on HDL.
abstract: OBJECTIVE
  Besides a significant reduction of low-density lipoprotein (LDL) cholesterol, statins moderately increase high-density lipoprotein (HDL) levels. In vitro studies have indicated that this effect may be the result of an increased expression of apolipoprotein (apo)A-I, the main protein component of HDL. The aim of the present study was to investigate in vivo the effect of rosuvastatin on apoA-I expression and secretion in a transgenic mouse model for human apoA-I.
  
  
  METHODS
  Human apoA-I transgenic mice were treated for 28 days with 5, 10 or 20 mg·kg(-1) ·day(-1) of rosuvastatin, the most effective statin in raising HDL levels. Possible changes of apoA-I expression by treatment were investigated by quantitative real-time RT-PCR on RNA extracted from mouse livers. The human apoA-I secretion rate was determined in primary hepatocytes isolated from transgenic mice from each group after treatment.
  
  
  RESULTS
  Rosuvastatin treatment with 5 and 10 mg·kg(-1) ·day(-1) did not affect apoA-I plasma levels, whereas a significant decrease was observed in mice treated with 20 mg·kg(-1) ·day(-1) of rosuvastatin (-16%, P < 0.01). Neither relative hepatic mRNA concentrations of apoA-I nor apoA-I secretion rates from primary hepatocytes were influenced by rosuvastatin treatment at each tested dose.
  
  
  CONCLUSIONS
  In human apoA-I transgenic mice, rosuvastatin treatment does not increase either apoA-I transcription and hepatic secretion, or apoA-I plasma levels. These results support the hypothesis that other mechanisms may account for the observed HDL increase induced by statin therapy in humans.
authors.affiliation: Department of Pharmacological Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Marchesi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Parolini
authors.forename: Silvia
authors.initials: S
authors.lastname: Caligari
authors.forename: Donatella
authors.initials: D
authors.lastname: Gilio
authors.forename: Stefano
authors.initials: S
authors.lastname: Manzini
authors.forename: Marco
authors.initials: M
authors.lastname: Busnelli
authors.forename: Paola
authors.initials: P
authors.lastname: Cinquanta
authors.forename: Marina
authors.initials: M
authors.lastname: Camera
authors.forename: Marta
authors.initials: M
authors.lastname: Brambilla
authors.forename: Cesare R
authors.initials: CR
authors.lastname: Sirtori
authors.forename: Giulia
authors.initials: G
authors.lastname: Chiesa
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049294:Phospholipid Transfer Proteins / Q000097:blood; D011743:Pyrimidines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D049294:Phospholipid Transfer Proteins; D011743:Pyrimidines; D013449:Sulfonamides; D014280:Triglycerides; C510091:phospholipid transfer protein, mouse; D000068718:Rosuvastatin Calcium; D002784:Cholesterol