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Rosuvastatin does not affect human apolipoprotein A‐I expression in genetically modified mice: a clue to the disputed effect of statins on HDL
Author(s) -
Marchesi Marta,
Parolini Cinzia,
Caligari Silvia,
Gilio Donatella,
Manzini Stefano,
Busnelli Marco,
Cinquanta Paola,
Camera Marina,
Brambilla Marta,
Sirtori Cesare R,
Chiesa Giulia
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01429.x
Subject(s) - rosuvastatin , apolipoprotein b , endocrinology , medicine , genetically modified mouse , transgene , secretion , lipoprotein , cholesterol , rosuvastatin calcium , in vivo , statin , chemistry , biology , biochemistry , gene , microbiology and biotechnology
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.