Department of Exercise Physiology, Beijing Sport University, Beijing, China.
Guangdong Provincial Key Laboratory of Sports and Health Promotion, Department of Sport and Health Sciences, Scientific Research Center, Guangzhou Sport University, Guangzhou, China.
Hypertens Res. 2018 Feb;41(2):96-103. doi: 10.1038/hr.2017.96. Epub 2017 Nov 2.
Promoter methylation is a key mechanism in the epigenetic reprogramming of gene expression patterns. Here, we investigated the contribution of DNA methylation and the associated expression and function of large-conductance Ca-activated K (BK) channel in mesenteric arteries when hypertension was superimposed on aging. Male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) at young (12 weeks), adult (36 weeks) and old (64 weeks) life stages were used. BK channel currents, BK channel activity in regulating vascular tone, and BK channel β1 subunit (BKβ1) function and expression were greater in mesenteric arteries from SHR than from age-matched WKY controls. Consistently, hypertension decreased CpG methylation of the BKβ1 promoter at all ages. Furthermore, aging triggered an increase in BKβ1 promoter methylation in both old WKY and SHR, with concomitant suppression of the β1 subunit and BK channel activity. Aging enhanced β1 gene promoter methylation and subunit expression without changing BK channel function between young and adult WKY animals. In contrast, aging did not alter CpG methylation but facilitated BK channel currents and upregulated BKβ1 expression and function in adult SHR. Taken together, our results provide compelling evidence that hypertension and aging exert opposing effects on DNA methylation at BKβ1 promoter, subsequently resulting in different β1 expression levels and functional modulation of mesenteric arterial contractility. Such information is useful in revealing the epigenetic regulation of BK channel function in vascular smooth muscle and in comprehensively understanding the molecular mechanisms in vascular physiology and pathophysiology.
启动子甲基化是基因表达模式表观遗传重编程的关键机制。在这里，我们研究了在高血压叠加衰老时，DNA 甲基化的贡献以及大电导钙激活钾 (BK) 通道的相关表达和功能在肠系膜动脉中的作用。雄性 Wistar-Kyoto (WKY) 大鼠和自发性高血压大鼠 (SHR) 在年轻 (12 周)、成年 (36 周) 和老年 (64 周) 三个生命阶段被用于研究。与年龄匹配的 WKY 对照组相比，SHR 的肠系膜动脉中 BK 通道电流、调节血管张力的 BK 通道活性以及 BK 通道 β1 亚基 (BKβ1) 的功能和表达更高。一致地，高血压在所有年龄段都降低了 BKβ1 启动子的 CpG 甲基化。此外，衰老在老年 WKY 和 SHR 中都引发了 BKβ1 启动子甲基化的增加，同时抑制了 β1 亚基和 BK 通道的活性。衰老增强了年轻和成年 WKY 动物之间 BKβ1 基因启动子的甲基化以及亚基的表达，但没有改变 BK 通道功能。相比之下，衰老并没有改变 CpG 甲基化，但促进了成年 SHR 中的 BK 通道电流以及上调了 BKβ1 的表达和功能。总之，我们的研究结果提供了令人信服的证据，表明高血压和衰老对 BKβ1 启动子的 DNA 甲基化产生了相反的影响，随后导致不同的 β1 表达水平和对肠系膜动脉收缩性的功能调节。这些信息对于揭示 BK 通道在血管平滑肌中的表观遗传调控以及全面理解血管生理学和病理生理学中的分子机制非常有用。
