| Background and purposeEssential hypertension is the most important risk factor of cardiovascular disease, there are approximately one in three adults are suffering this disease. As reported by a recent survey in our country, the prevalence of hypertension in China is 33%, and it is increasing year by year. Essential hypertension (EH) is a complicate disease resulted from the interaction of life style, environment factors and genetic factors. Although twin and family studies highlight a clear inherited component to EH, the current purely sequence-based approach only accounts for a fraction of the genetic risk of the disease as evidenced by the recent genome-wide association studiesin which the identified genetic variants explain less than 1% of the blood pressure (BP) variation in the population. Obviously, the traditional Mendel’s law is not powerful to explain the pathogenesis of EH.Several epidemiological and clinical peculiarities of EH such as the incomplete concordance between monozygotic twins and its late onset and progressive nature, are difficult to explain with traditional DNA sequence-based approaches. These observations may indicate the involvement of epigenetic factors in EH development. Epigenetics refers to all meiotically and mitotically heritable changes in gene expression that are not coded in the DNA sequence itself. Epigenetic modifications include DNA methylation, histone acetylation and so on. There are several animal studies indicating that DNA methylation plays an important role in the pathogenesis of EH so far. However, to date, very few studies explored the role of methylation in the development of human EH. Based on several recent studies which indicated that inflammation played a role in the development of pathogenesis of EH, we hypothesized that changes in DNA methylation of leukocytes are involved in the development of EH. In this study, we managed to explore the role of DNA methylation in WBC in EH through DNA methylation chips and expression profile chips. Then we will verify the function of target gene in hypertension in vitro.MethodsOur study is consisted of 13 pure hypertension patients and 13 age and gender matched control volunteers. All individuals are more than 50 years old and none of them are suffering cardiovascular and cerebrovascular events. The standards of pure hypertension group are as follows:(1) systolic pressure≥160 mmHg or diastolic pressure≥100 mmHg or individuals who are under treatment of antihypertensive drugs;(2) 18.5 kg/m2≤ BMI≤24 kg/m2. The standards of normal controls are as follows:(1) systolic pressure< 140 mmHg or diastolic pressure<90 mmHg; (2) 18.5 kg/m2≤BMI ≤24 kg/m2 。Then the DNA and RNA of peripheral blood leukocytes were extracted to carry out genome wide methylation association study and expression profile chips respectively. After discovery of the different gene, we deeply verify the function of it in hypertension in HK-2 cells.ResultsAs indicated in the methylation chip, compared with the normal controls, the methylation level of one site in MAP2K3 gene was decreased in hypertension group, but the difference is not significant. Subsequently, our expression profile chips showed that the mRNA expression level was also up-regulated in hypertension group. Subsequently, our cellular experiment suggested that MAP2K3/p38 pathway was involved in the regulation of AngⅡ on the expression of ACE/ACE2.ConclusionsThe identification of a difference in blood leukocyte DNA methylation site and the different expression level of MAP2K3 gene suggested together that methylation of MAP2K3 gene may play a critical role in the pathogenesis of hypertension. Our cellular... |
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