Atorvastatin and hormone therapy influence expression of ABCA1, APOA1 and SCARB1 in mononuclear cells from hypercholesterolemic postmenopausal women

https://doi.org/10.1016/j.jsbmb.2013.08.017Get rights and content

Highlights

  • We studied RCT related genes in postmenopausal women under atorvastatin and hormone replacement.

  • Hormone therapy plus atorvastatin association treatment had a better impact in improving the lipid profile.

  • ABCA1 expression in PBMC was down-regulated by atorvastatin, hormone therapy and their combination.

  • Atorvastatin reduced APOA1 expression whereas hormone therapy reduced SCARB1 expression.

  • LXRA was correlated with ABCA1, APOA1 and SCARB1 RNAm values before and after treatments.

Abstract

Background

Reverse cholesterol transport (RCT) has been inversely related to atherosclerosis and cardiovascular risk. The influence of menopause in the RCT process is poorly understood and the effects of cholesterol-lowering interventions, including statins and hormone therapy (HT), on genes controlling the RCT in postmenopausal women are also unknown.

Methods

The effects on serum lipids and expression profile of genes involved in RCT – APOA1, ABCA1, ABCG1, SCARB1 and LXRA – were evaluated by TaqMan® quantitative PCR in peripheral blood mononuclear cells (PBMC) from 87 postmenopausal hypercholesterolemic women treated with atorvastatin (AT, n = 17), estrogen or estrogen plus progestin (HT, n = 34) and estrogen or estrogen plus progestin associated with atorvastatin (HT + AT, n = 36).

Results

Atorvastatin and HT treatments reduced the mRNA levels of APOA1 and SCARB1, respectively, whereas ABCA1 expression was reduced after all treatments. Although the expression of LXRA, an important transcription factor controlling the expression of genes involved in RCT, was not modified after any treatment, it was correlated with ABCA1, APOA1 and SCARB1 RNAm values before and after treatments, however no correlation with ABCG1 was observed. In a linear regression analysis, HT was related to an increase in apoAI levels after treatment when compared to atorvastatin and, moreover, higher SCARB1 and ABCA1 basal expression were also associated with decreased apoAI levels after treatments.

Conclusion

ABCA1 mRNA levels are decreased by atorvastatin and HT, however these treatments have a differential effect on APOA1 and SCARB1 expression in PBMC from postmenopausal women. Basal ABCA1 and SCARB1 expression profile could be helpful markers in predicting the effect of atorvastatin and HT on RCT, according to the changes in apoAI levels in this sample population.

Introduction

Menopause is associated with changes in lipid levels that result in an increased risk for development of cardiovascular heart diseases (CHD). In postmenopausal women, the increased plasma low density lipoprotein (LDL) cholesterol and triglycerides and reduced high density lipoprotein (HDL) cholesterol result in an increased risk of atherosclerosis and cardiovascular events [1].

Hormone therapy (HT) has been used in primary and secondary prevention of CHD in postmenopausal women, however its long term efficiency remains controversial [2]. The influence of HT on serum lipids, decreasing total and LDL cholesterol and raising HDL cholesterol, support its beneficial cardiovascular effects [3].

Inhibitors of endogenous cholesterol synthesis by competitive inhibition of hydroxy-3-methylglutaril-coenzyme A reductase (HMGCR), known as statins, have been described by numerous clinical trials to reduce cardiovascular events due to their LDL cholesterol-lowering effects [4]. Nevertheless, statin effects on hypercholesterolemic postmenopausal women have been poorly investigated.

HDL cholesterol levels have been inversely associated with the development of atherosclerosis and cardiovascular diseases. Anti-atherogenic proprieties of HDL particles are attributable mainly to their involvement in the reverse cholesterol transport (RCT), a process that mobilizes the excess of cholesterol stored in peripheral tissues to the liver for excretion into the bile [5]. RCT initiates with cholesterol efflux from peripheral cells to lipid-poor apolipoprotein AI (apoAI) particles in a process mediated by the membrane transporter ATP binding cassette A1 (ABCA1) and, to some extent, ATP binding cassette G1 (ABCG1) and scavenger receptor class B type I (SR-BI). After enzymatic maturation of nascent HDL particles in plasma, they are taken up by the specific HDL receptor SR-BI in the liver, for further excretion into the bile [5].

The oxysterol sensitive transcription factors from the LXR family have been related to the transcriptional activity of genes participating in the lipid metabolism and RCT in monocytes [6]. Particularly, LXRα regulates the transcriptional activity of genes involved in cholesterol efflux [7]. Lipid-lowering drugs have been shown to reduce the bioavailability of oxysterols in human macrophages [8], which could affect the LXRα target genes involved in cholesterol efflux.

The influence of menopause on RCT is poorly understood and the potential beneficial effects of lipid-lowering pharmacological interventions in postmenopausal women are also unknown. Our group and others have previously reported the effects of statins on RCT related genes in hypercholesterolemic individuals using peripheral blood mononuclear cells (PBMC) as a useful study model to evaluate the expression of genes involved in cholesterol efflux [9], [10]

In this study, we evaluated the effects of HT and atorvastatin treatment on the gene expression profile of APOA1, ABCA1, ABCG1, the SR-BI gene (SCARB1) and LXRA in PBMC from hypercholesterolemic postmenopausal women and their implication in the modulation of the RCT plasma markers, HDL cholesterol and apoAI.

Section snippets

Subjects and study protocol

Eighty seven natural postmenopausal, hypercholesterolemic and Caucasian-descent Brazilian women were selected at the Dyslipidemia Department of the Dante Pazzanese Institute of Cardiology (Sao Paulo City, Brazil) from 2003 to 2005. The selection criteria and main characteristics of the study population have been previously reported [11].

All participants had LDL cholesterol higher than 130 mg/dL (3.36 mmol/L), even after a wash-out period of four weeks on a low-fat diet, oriented by nutritionists.

Results

Clinical characteristics and serum lipids at the baseline for postmenopausal women groups were previously published [11] and they are presented in Table 1. Total cholesterol, LDL cholesterol and apoB concentrations were reduced after all of the treatments. Triglycerides, VLDL cholesterol and apoAI were reduced after the atorvastatin treatment, whereas triglycerides and VLDL cholesterol were increased in the HT group. After the treatments, patients using atorvastatin (AT and HT + AT groups) showed

Discussion

Cholesterol-lowering effects of both, HT and statins, have been previously described in postmenopausal hypercholesterolemic women [13], [14], whereas the influence of these pharmacological interventions on RCT is less understood. In this study, the HT plus atorvastatin treatment had a better impact in improving the lipid profile and avoiding negative effects of atorvastatin on RCT, as the reduction of apoAI levels observed with the atorvastatin monotherapy, despite feeble direct benefits on HDL

Conclusions

Atorvastatin and HT have a differential impact in the expression of genes involved in cholesterol efflux from monocyte/macrophages. Whereas ABCA1 is decreased by atorvastatin and HT, APOA1 is decreased after atorvastatin and SCARB1 is down regulated by HT in PBMC from postmenopausal women. The basal ABCA1 and SCARB1 expression profile could be helpful markers in predicting the effect from atorvastatin and HT on RCT, according to the change of apoAI levels in this population. Moreover, the use

Acknowledgements

The present study was supported by grants from CNPq (Protocol # 303034/2009-2) and FAPESP (2009/15125-8). We thank the volunteers for their participation and physicians and nurses from The Dyslipidemia Department from the Dante Pazzanese Institute of Cardiology for technical support during patient selection. We also thank Diego Gallardo for his valuable support in the statistical analysis. A. Cerda is a recipient of a fellowship from CONICYT, Chile. M.H. Issa, F.D.V. Genvigir and S.A. Cavalli

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