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Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia.

ABSTRACT: Oxysterols (OHC) are biologically active cholesterol metabolites circulating in plasma that may be formed enzymatically (e.g. 24S-OHC, 25-OHC and 27-OHC) or by autoxidative mechanisms (e.g. 7-ketocholesterol, 7?-OHC and 25-OHC). Oxysterols are more soluble than cholesterol and are reported to exert inflammatory, cytoprotective and apoptotic effects according to concentration and species. Esterified oxysterols have been analysed in people with dementia and cardiovascular diseases although there is no consistent relationship between oxysterol esters and disease. However, oxysterol esters are held in lipoprotein core and may not relate to the concentration and activity of plasma free oxysterols. Methodological limitations have challenged the analysis of free oxysterols to date. We have developed a fast, sensitive and specific quantitative LC-MS/MS, multiple reaction monitoring (MRM) method to target five oxysterols in human plasma with analyte recoveries between 72% and 82% and sensitivities between 5 and 135?pg/ml. A novel method was used to investigate the hypothesis that simvastatin may reduce the concentrations of specific plasma free oxysterols in hypercholesterolaemia. Twenty healthy male volunteers were recruited (aged 41-63 years); ten were asymptomatic with high plasma cholesterol >?6.5?mM and ten were healthy with normal plasma cholesterol (

SUBMITTER: Dias IHK

PROVIDER: S-EPMC5952874 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other

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Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia.

Dias Irundika H K IHK Milic Ivana I Lip Gregory Y H GYH Devitt Andrew A Polidori M Cristina MC Griffiths Helen R HR

Redox biology 20180217

Oxysterols (OHC) are biologically active cholesterol metabolites circulating in plasma that may be formed enzymatically (e.g. 24S-OHC, 25-OHC and 27-OHC) or by autoxidative mechanisms (e.g. 7-ketocholesterol, 7β-OHC and 25-OHC). Oxysterols are more soluble than cholesterol and are reported to exert inflammatory, cytoprotective and apoptotic effects according to concentration and species. Esterified oxysterols have been analysed in people with dementia and cardiovascular diseases although there i ...[more]

PMID: 29501047

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Project description:BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted inhibitor of the low-density lipoprotein (LDL) receptor and an important regulator of LDL metabolism. Elevated PCSK9 levels have been associated with cardiovascular risk. The purpose of this study was to investigate how ezetimibe and simvastatin, alone and in combination, affect PCSK9 circulating concentrations.MethodsA single center, randomized, open-label parallel 3-group study in healthy men (mean age 32±9 years, body mass index 25.7±3.2 kg/m(2)) was performed. Each group of 24 subjects was treated for 14 days with either simvastatin 40 mg/d, ezetimibe 10 mg/d, or with both drugs. Multivariate analysis was used to investigate parameters influencing the change in PCSK9 concentrations under treatment.ResultsThe baseline plasma PCSK9 concentrations in the total cohort were 52±20 ng/mL with no statistically significant differences between the groups. They were increased by 68±85% by simvastatin (P?=?0.0014), by 10±38% by ezetimibe (P?=?0.51) and by 67±91% by simvastatin plus ezetimibe (P?=?0.0013). The increase in PCSK9 was inversely correlated with baseline PCSK9 concentrations (Spearman's R?=?-0.47, P<0.0001) and with the percent change in LDL cholesterol concentrations (Spearman's R?=?-0.30, P<0.01). In multivariate analyses, only baseline PCSK9 concentrations (??=?-1.68, t?=?-4.04, P<0.0001), percent change in LDL cholesterol from baseline (??=?1.94, t?=?2.52, P?=?0.014), and treatment with simvastatin (P?=?0.016), but not ezetimibe (P?=?0.42), significantly influenced changes in PCSK9 levels. Parameters without effect on PCSK9 concentration changes were age, body mass index, body composition, thyroid function, kidney function, glucose metabolism parameters, adipokines, markers of cholesterol synthesis and absorption, and molecular markers of cholesterol metabolism.ConclusionsEzetimibe does not increase circulating PCSK9 concentrations while simvastatin does. When added to simvastatin, ezetimibe does not cause an incremental increase in PCSK9 concentrations. Changes in PCSK9 concentrations are tightly regulated and mainly influenced by baseline PCSK9 levels and changes in LDL cholesterol.Trial registrationClinicalTrials.gov NCT00317993.

Dataset Information

Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia.

Publications

Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia.

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