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.
Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice: a clue to the disputed effect of statins on HDL / M. Marchesi, C. Parolini, S. Caligari, D. Gilio, S. Manzini, M. Busnelli, P. Cinquanta, M. Camera, M. Brambilla, C.R. Sirtori, G. Chiesa. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - 164:5(2011), pp. 1460-1468. [10.1111/j.1476-5381.2011.01429.x]
Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice: a clue to the disputed effect of statins on HDL
C. Parolini;S. Manzini;M. Busnelli;M. Camera;M. Brambilla;C.R. SirtoriPenultimo
;G. ChiesaUltimo
2011
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.File | Dimensione | Formato | |
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