RESUMO
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.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/metabolismo , Ácidos Heptanoicos/uso terapêutico , Leucócitos Mononucleares/metabolismo , Pirróis/uso terapêutico , Receptores Depuradores Classe B/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Anticolesterolemiantes/administração & dosagem , Apolipoproteína A-I/genética , Atorvastatina , Células Cultivadas , Estradiol/uso terapêutico , Feminino , Ácidos Heptanoicos/administração & dosagem , Compostos Heterocíclicos/uso terapêutico , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Pessoa de Meia-Idade , Pós-Menopausa , Pirróis/administração & dosagem , Receptores Depuradores Classe B/genética , TranscriptomaRESUMO
Menopause is associated with changes in lipid levels resulting in increased risk of atherosclerosis and cardiovascular events. Hormone therapy (HT) and atorvastatin have been used to improve lipid profile in postmenopausal women. Effects of HT, atorvastatin and APOE polymorphisms on serum lipids and APOE and LXRA expression were evaluated in 87 hypercholesterolemic postmenopausal women, randomly selected for treatment with atorvastatin (AT, n=17), estrogen or estrogen plus progestagen (HT, n=34) and estrogen or estrogen plus progestagen associated with atorvastatin (HT+AT, n=36). RNA was extracted from peripheral blood mononuclear cells (PBMC) and mRNA expression was measured by TaqMan(®) PCR. APOE É2/É3/É4 genotyping was performed using PCR-RFLP. Total cholesterol (TC), LDL-c and apoB were reduced after each treatment (p<0.001). Triglycerides, VLDL-c and apoAI were reduced only after atorvastatin (p<0.05), whereas triglycerides and VLDL-c were increased after HT (p=0.01). HT women had lower reduction on TC, LDL-c and apoB than AT and HT+AT groups (p<0.05). APOE mRNA expression was reduced after atorvastatin treatment (p=0.03). Although LXRA gene expression was not modified by atorvastatin, it was correlated with APOE mRNA before and after treatments. Basal APOE mRNA expression was not influenced by gene polymorphisms, however the reduction on APOE expression was more pronounced in É3É3 than in É3É4 carriers. Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMC from postmenopausal women.
Assuntos
Apolipoproteínas E/metabolismo , Regulação para Baixo/efeitos dos fármacos , Terapia de Reposição de Estrogênios , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pós-Menopausa , Pirróis/uso terapêutico , Idoso , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Apolipoproteínas/sangue , Apolipoproteínas E/genética , Atorvastatina , Brasil , LDL-Colesterol/sangue , Quimioterapia Combinada/efeitos adversos , Terapia de Reposição de Estrogênios/efeitos adversos , Terapia de Reposição de Estrogênios/métodos , Feminino , Ácidos Heptanoicos/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/sangue , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Receptores X do Fígado , Pessoa de Meia-Idade , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Polimorfismo de Nucleotídeo Único , Pirróis/efeitos adversos , RNA Mensageiro/metabolismoRESUMO
Menopause is associated with changes in lipid levels resulting in increased risk of atherosclerosis andcardiovascular events. Hormone therapy (HT) and atorvastatin have been used to improve lipid profilein postmenopausal women.Effects of HT, atorvastatin and APOE polymorphisms on serum lipids and APOE and LXRA expressionwere evaluated in 87 hypercholesterolemic postmenopausal women, randomly selected for treatmentwith atorvastatin (AT, n = 17), estrogen or estrogen plus progestagen (HT, n = 34) and estrogen or estrogenplus progestagen associated with atorvastatin (HT + AT, n = 36). RNA was extracted from peripheralblood mononuclear cells (PBMC) and mRNA expression was measured by TaqMan® PCR. APOE 2/ 3/ 4genotyping was performed using PCR-RFLP.Total cholesterol (TC), LDL-c and apoB were reduced after each treatment (p < 0.001). Triglycerides,VLDL-c and apoAI were reduced only after atorvastatin (p < 0.05), whereas triglycerides and VLDL-c wereincreased after HT (p = 0.01). HT women had lower reduction on TC, LDL-c and apoB than AT and HT + ATgroups (p < 0.05). APOE mRNA expression was reduced after atorvastatin treatment (p = 0.03). AlthoughLXRA gene expression was not modified by atorvastatin, it was correlated with APOE mRNA before andafter treatments. Basal APOE mRNA expression was not influenced by gene polymorphisms, however thereduction on APOE expression was more pronounced in 3 3 than in 3 4 carriers.Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMCfrom postmenopausal women.
