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|Title:||Methylation of adrenergic <img src='/image/spc_char/beta.gif' border=0>1 receptor is a potential epigenetic mechanism controlling antihypertensive response to metoprolol|
<img src='/image/spc_char/beta.gif' border=0>1-Adrenergic receptor
|Abstract:||Although metoprolol is used to treat hypertension, clinical responses are variable and unpredictable. Evidence suggests that adrenergic <img src='/image/spc_char/beta.gif' border=0>1 receptor (<i>ADRB1</i>, designated <i>Adrb1</i> in rodents) gene polymorphisms influence the level of blood pressure response to this drug therapy, but their presence can not predict the response of the individual patient. The question exists whether epigenetic modifications, such as DNA methylation could cause changes in the gene’s expression that are a determining factor in metoprolol’s efficacy. The aim of this study was to verify whether DNA methylation could change the expression of the <i style="">ADRB1</i> gene, and epigenetic modification could explain why individuals with identical<i style=""> ADRB1</i> gene polymorphisms have different antihypertensive responses to metoprolol. H9c2 rat myocardial cells <i style="">in vitro</i> were randomly divided into 5-aza-2'-deoxycytidine (decitabine)-treated (0.5 to 10.0 μM) and control groups. For the <i style="">in vivo</i> experiments, 45 spontaneously hypertensive rats (SHRs) were divided into metoprolol-treated and control groups, and after a 4-week intervention myocardia were harvested. Genomic methylation-sensitive PCR was used to assess the methylation status of the <i style="">Adrb1</i> promoter after DNA extraction from H9c2 cells and SHR myocardia. Real-time fluorescent quantitative RT-PCR was used to determine levels of <i style="">Adrb1</i> mRNA. In H9c2 cells, the least degree of methylation was observed in the 5.0 μM decitabine treated group. Prolonged exposure of cells to 5.0 μM decitabine resulted in downregulating methylation of the <i style="">Adrb1</i> promoter. Increased levels of <i style="">Adrb1</i> mRNA of the 5.0 μM group demonstrated that this concentration resulted in the highest expression. Accordingly, DNA methylation resulted in the downregulation of <i style="">Adrb1</i> transcription. <i style="">In vivo</i>, the lower level of methylation of the <i style="">Adrb1</i> promoter from SHR myocardial samples demonstrated a better antihypertensive effect by metoprolol. The expression of <i style="">Adrb1</i> mRNA in the effective group of SHRs was significantly upregulated. In conclusion, as shown in both H9c2 cells and SHRs, downregulated methylation of the <i style="">Adrb1</i> promoter is likely to improve the antihypertensive efficacy of metoprolol.|
|ISSN:||0975-0959 (Online); 0301-1208 (Print)|
|Appears in Collections:||IJBB Vol.48(5) [October 2011]|
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