Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice: A clue to the disputed effect of statins on HDL

Marta Marchesi, Cinzia Parolini, Silvia Caligari, Donatella Gilio, Stefano Manzini, Marco Busnelli, Paola Cinquanta, Marina Camera, Marta Brambilla, Cesare R. Sirtori, Giulia Chiesa

Research output: Contribution to journalArticle

Abstract

Background and Purpose 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. Experimental Approach 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. Key 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 and Implications 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.

Original languageEnglish
Pages (from-to)1460-1468
Number of pages9
JournalBritish Journal of Pharmacology
Volume164
Issue number5
DOIs
Publication statusPublished - Nov 2011

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Apolipoprotein A-I
HDL Lipoproteins
Transgenic Mice
human APOA1 protein
Rosuvastatin Calcium
Hepatocytes
Liver
LDL Cholesterol
Real-Time Polymerase Chain Reaction

Keywords

  • cholesterol
  • HDL
  • human apolipoprotein A-I
  • rosuvastatin
  • transgenic mice

ASJC Scopus subject areas

  • Pharmacology

Cite this

Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice : A clue to the disputed effect of statins on HDL. / Marchesi, Marta; Parolini, Cinzia; Caligari, Silvia; Gilio, Donatella; Manzini, Stefano; Busnelli, Marco; Cinquanta, Paola; Camera, Marina; Brambilla, Marta; Sirtori, Cesare R.; Chiesa, Giulia.

In: British Journal of Pharmacology, Vol. 164, No. 5, 11.2011, p. 1460-1468.

Research output: Contribution to journalArticle

Marchesi, Marta ; Parolini, Cinzia ; Caligari, Silvia ; Gilio, Donatella ; Manzini, Stefano ; Busnelli, Marco ; Cinquanta, Paola ; Camera, Marina ; Brambilla, Marta ; Sirtori, Cesare R. ; Chiesa, Giulia. / Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice : A clue to the disputed effect of statins on HDL. In: British Journal of Pharmacology. 2011 ; Vol. 164, No. 5. pp. 1460-1468.
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abstract = "Background and Purpose 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. Experimental Approach 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. Key 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 and Implications 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.",
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T1 - Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice

T2 - A clue to the disputed effect of statins on HDL

AU - Marchesi, Marta

AU - Parolini, Cinzia

AU - Caligari, Silvia

AU - Gilio, Donatella

AU - Manzini, Stefano

AU - Busnelli, Marco

AU - Cinquanta, Paola

AU - Camera, Marina

AU - Brambilla, Marta

AU - Sirtori, Cesare R.

AU - Chiesa, Giulia

PY - 2011/11

Y1 - 2011/11

N2 - Background and Purpose 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. Experimental Approach 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. Key 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 and Implications 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.

AB - Background and Purpose 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. Experimental Approach 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. Key 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 and Implications 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.

KW - cholesterol

KW - HDL

KW - human apolipoprotein A-I

KW - rosuvastatin

KW - transgenic mice

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