β1亚基启动子区甲基化在高血压和增龄调控肠系膜动脉BKCa通道功能中的作用
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(北京体育大学运动与体质健康教育部重点实验室,北京市 100084)

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张慧荣,硕士研究生,研究方向为运动和心血管生理学,E-mail为m18612362395@163.com。通信作者石丽君,教授,博士研究生导师,研究方向为运动和心血管生理学,E-mail为l_j_shi72@163.com。

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国家自然科学基金项目(31771312);中央高校科研业务费专项资金资助项目(2018GJ010)


Role of β1 submit promoter methylation when hypertension and aging regulate the activity of large-conductance Ca2+-activated K+ channel in mesenteric arteries
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Key Laboratory of Sports and Physical Health Ministry of Education, Beijing Sport University, Beijing 100084, China)

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    摘要:

    目的 探讨高血压和增龄对大鼠肠系膜动脉平滑肌细胞大电导钙激活钾通道(BKCa) β1亚基甲基化程度的影响。方法 选用3、16月龄雄性正常血压大鼠(WKY)和自发性高血压大鼠(SHR),尾动脉无创测定血压,取各组大鼠肠系膜动脉进行实验。分别采用膜片钳全细胞模式记录BKCa通道电流、单通道检测BKCa通道门控特性;离体微血管张力测定BKCa通道在血管张力中的作用;蛋白免疫印迹观察BKCa通道α、β1亚基表达情况;亚硫酸氢盐测序PCR测定β1亚基启动子区甲基化程度。结果 3月龄时SHR的BKCa通道平均电流密度较同龄WKY显著增大;WKY、SHR的BKCa通道平均电流密度随增龄均显著降低。高血压时,他莫昔芬诱发的BKCa通道开放概率增加显著高于WKY;此外,BKCa通道在血管张力调节中的贡献率亦显著高于同龄WKY。BKCa通道β1亚基表达在高血压时发生显著上调,随增龄变化,β1亚基表达在正常血压和高血压中均发生下调。高血压降低了β1亚基启动子区甲基化程度,而增龄增加了其甲基化程度。结论 高血压时,BKCa通道β1亚基启动子区发生去甲基化,β1亚基表达增多,BKCa通道功能增强;而在增龄过程中,β1亚基启动子区发生甲基化,其表达减少,BKCa通道功能减弱。

    Abstract:

    Aim To explore the role of β1 submit promoter methylation when hypertension and aging regulate the activity of large-conductance Ca2+-activated K+ channel in mesenteric arteries. Methods Male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were studied at 3,6 months of age, blood pressure was noninvasively measured in the caudal artery, the mesenteric arteries were taken for the experiment. The whole-cell K+ currents and BKCa single channel currents were measured using whole-cell and inside-out patch, respectively. Isometric contraction study was performed to investigate the contribution of BKCa channel to vascular tone regulation. Western blot was used to detect the expression of α and β1 submit of BKCa channel in mesenteric arteries. DNA bisulfite sequencing PCR was performed to investigate of the DNA methylation status at β1 gene (KCNMB1) promoter. Results At 3 months old, compared to WKY, the mean peak BKCa current density of SHR was significantly increased. Aging decreased the mean peak whole-cell current density of both SHR and WKY. The increases in the Po of BKCa channels that tamoxifen evoked in WKY were significantly lower than those of age-matched SHR. Meantime, hypertension increased the contribution of BKCa channels in vascular tone regulation. Compared with age-matched WKY, the protein expression level of the β1 subunit observed in SHR was always significantly increased. Aging reduced β1 subunit expression in mesenteric arteries. Hypertension decreased BKCa channel β1 submit promoter methylation in mesenteric arteries, in contrast, aging increased BKCa channel β1 submit promoter methylation in mesenteric arteries. Conclusions During hypertension, KCNMB1 gene demethylated and the expression of β1 submit increased, which enhanced the function of BKCa channel. Aging not only enhanced CpG methylation at KCNMB1 gene promoter but also upregulated β1 subunit expression, which diminished the function of BKCa channel.

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张慧荣,张严焱,李珊珊,石丽君.β1亚基启动子区甲基化在高血压和增龄调控肠系膜动脉BKCa通道功能中的作用[J].中国动脉硬化杂志,2018,26(10):980~986, 1005.

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  • 收稿日期:2018-06-06
  • 最后修改日期:2018-09-27
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  • 在线发布日期: 2018-11-09