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Oviductal Glycoprotein 1 Promotes Hypertension by Inducing Vascular Remodeling Through an Interaction With MYH9
Circulation ( IF 35.5 ) Pub Date : 2022-09-29 , DOI: 10.1161/circulationaha.121.057178
Congxia Bai 1, 2 , Ming Su 3 , Yaohua Zhang 1, 4 , Yahui Lin 5 , Yingying Sun 1 , Li Song 1 , Ning Xiao 1 , Haochen Xu 1 , Hongyan Wen 1 , Meng Zhang 1 , Jiedan Ping 1 , Jing Liu 1 , Rutai Hui 1 , Hao Li 1 , Jingzhou Chen 1, 6
Affiliation  

Background:Hypertension is a common cardiovascular disease that is related to genetic and environmental factors, but its mechanisms remain unclear. DNA methylation, a classic epigenetic modification, not only regulates gene expression but is also susceptible to environmental factors, linking environmental factors to genetic modification. Therefore, globally screening differential genomic DNA methylation in patients with hypertension is important for investigating hypertension mechanisms.Methods:Differential genomic DNA methylation in patients with hypertension, individuals with prehypertension, and healthy control individuals was screened using Illumina 450K BeadChip and verified by pyrosequencing. Plasma OVGP1 (oviduct glycoprotein 1) levels were determined using an enzyme-linked immunosorbent assay. Ovgp1 transgenic and knockout mice were generated to analyze the function of OVGP1. The blood pressure levels of the mouse models were measured using the tail-cuff system and radiotelemetry methods. The role of OVGP1 in vascular remodeling was determined by vascular relaxation studies. Protein–protein interactions were investigated using a pull-down/mass spectrometry assay and verified with coimmunoprecipitation and pull-down assays.Results:We found a hypomethylated site at cg20823859 in the promoter region of OVGP1 and plasma OVGP1 levels were significantly increased in patients with hypertension. This finding indicates that OVGP1 is associated with hypertension. In Ovgp1 transgenic mice, OVGP1 overexpression caused an increase in blood pressure, dysfunctional vasoconstriction and vasodilation, remodeling of arterial walls, and increased vascular superoxide stress and inflammation, and these phenomena were exacerbated by angiotensin II infusion. In contrast, OVGP1 deficiency attenuated angiotensin II–induced vascular oxidase stress, inflammation, and collagen deposition. These findings indicate that OVGP1 is a prohypertensive factor that directly promotes vascular remodeling. Pull-down and coimmunoprecipitation assays showed that MYH9 (nonmuscle myosin heavy chain IIA) interacted with OVGP1, whereas inhibition of MYH9 attenuated OVGP1-induced hypertension and vascular remodeling.Conclusions:Hypomethylation at cg20823859 in the promoter region of OVGP1 is associated with hypertension and induces upregulation of OVGP1. The interaction between OVGP1 and MYH9 contributes to vascular remodeling and dysfunction. Therefore, OVGP1 is a prohypertensive factor that promotes vascular remodeling by binding with MYH9.

中文翻译:

输卵管糖蛋白 1 通过与 MYH9 的相互作用诱导血管重塑来促进高血压

背景:高血压是一种常见的心血管疾病,与遗传和环境因素有关,但其发病机制尚不清楚。DNA甲基化是一种经典的表观遗传修饰,不仅调节基因表达,而且易受环境因素的影响,将环境因素与基因修饰联系起来。因此,全球筛查高血压患者的差异基因组 DNA 甲基化对于研究高血压机制非常重要。方法:使用 Illumina 450K BeadChip 筛选高血压患者、高血压前期个体和健康对照个体的差异基因组 DNA 甲基化,并通过焦磷酸测序验证。使用酶联免疫吸附测定法测定血浆 OVGP1(输卵管糖蛋白 1)水平。OVGP1产生转基因和敲除小鼠以分析OVGP1的功能。使用尾套系统和无线电遥测法测量小鼠模型的血压水平。OVGP1 在血管重塑中的作用由血管松弛研究确定。使用下拉/质谱分析研究蛋白质-蛋白质相互作用,并通过免疫共沉淀和下拉分析进行验证。结果:我们在 OVGP1 的启动子区域中发现了 cg20823859 的低甲基化位点,并且血浆 OVGP1 水平显着增加。高血压。这一发现表明 OVGP1 与高血压有关。在Ovgp1 中在转基因小鼠中,OVGP1 过表达导致血压升高、血管收缩和血管舒张功能失调、动脉壁重塑以及血管超氧化物应激和炎症增加,而血管紧张素 II 输注加剧了这些现象。相比之下,OVGP1 缺乏会减弱血管紧张素 II 诱导的血管氧化酶应激、炎症和胶原蛋白沉积。这些发现表明 OVGP1 是一种直接促进血管重塑的降压因子。Pull-down 和免疫共沉淀试验表明 MYH9(非肌肉肌球蛋白重链 IIA)与 OVGP1 相互作用,而 MYH9 的抑制减弱了 OVGP1 诱导的高血压和血管重塑。结论:OVGP1 启动子区cg20823859的低甲基化与高血压有关并诱导 OVGP1 的上调。OVGP1 和 MYH9 之间的相互作用有助于血管重塑和功能障碍。因此,OVGP1 是一种通过与 MYH9 结合来促进血管重塑的降压因子。
更新日期:2022-09-29
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