Gstp1 negatively regulates blood pressure in hypertensive rat via promoting APLNR ubiquitination degradation mediated by Nedd4.

IF 6.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Jianzhen Lei, Fen Zheng, Luyao Chen, Ruyi Zhang, Yang Yang, Zhimin Yin, Lan Luo
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Abstract

Hypertension is a leading risk factor for disease burden worldwide. Vascular contraction and remodeling contribute to the development of hypertension. Glutathione S-transferase P1 (Gstp1) plays several critical roles in both normal and neoplastic cells. In this study, we investigated the effect of Gstp1 on hypertension as well as on vascular smooth muscle cell (VSMC) contraction and phenotypic switching. We identified the higher level of Gstp1 in arteries and VSMCs from hypertensive rats compared with normotensive rats for the first time. We then developed Adeno-associated virus 9 (AAV9) mediated Gstp1 down-regulation and overexpression in rats and measured rat blood pressure by using the tail-cuff and the carotid catheter method. We found that the blood pressure of spontaneously hypertensive rats (SHR) rose significantly with Gstp1 down-regulation and reduced apparently after Gstp1 overexpression. Similar results were obtained from the observations of 2-kidney-1-clip renovascular (2K1C) hypertensive rats. Gstp1 did not influence blood pressure of normotensive Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats. Further in vitro study indicated that Gstp1 knockdown in SHR-VSMCs promoted cell proliferation, migration, dedifferentiation and contraction, while Gstp1 overexpression showed opposite effects. Results from bioinformatic analysis showed that the Apelin/APLNR system was involved in the effect of Gstp1 on SHR-VSMCs. The rise in blood pressure of SHR induced by Gstp1 knockdown could be reversed by APLNR antagonist F13A. We further found that Gstp1 enhanced the association between APLNR and Nedd4 E3 ubiquitin ligases to induce APLNR ubiquitination degradation. Thus, in the present study, we discovered a novel anti-hypertensive role of Gstp1 in hypertensive rats and provided the experimental basis for designing an effective anti-hypertensive therapeutic strategy.

Gstp1 通过促进 Nedd4 介导的 APLNR 泛素化降解,对高血压大鼠的血压进行负向调节。
高血压是造成全球疾病负担的主要风险因素。血管收缩和重塑是高血压发病的原因之一。谷胱甘肽 S 转移酶 P1(Gstp1)在正常细胞和肿瘤细胞中发挥着多种关键作用。在这项研究中,我们探讨了 Gstp1 对高血压以及血管平滑肌细胞(VSMC)收缩和表型转换的影响。我们首次发现,与正常血压大鼠相比,高血压大鼠动脉和血管平滑肌细胞中的 Gstp1 水平更高。随后,我们开发了腺相关病毒 9(AAV9)介导的大鼠 Gstp1 下调和过表达技术,并采用尾套法和颈动脉导管法测定了大鼠的血压。我们发现,Gstp1 下调后,自发性高血压大鼠(SHR)和双肾一夹(2K1C)新血管性高血压大鼠的血压明显升高;Gstp1 过表达后,血压明显降低。Gstp1 不影响正常血压的 Wistar-Kyoto (WKY) 大鼠和 Sprague-Dawley (SD) 大鼠的血压。进一步的体外研究表明,在 SHR-VSMCs 中敲除 Gstp1 可促进细胞增殖、迁移、去分化和收缩。生物信息学分析结果表明,Apelin/APLNR 系统参与了 Gstp1 对 SHR-VSMCs 的影响。APLNR 拮抗剂 F13A 可逆转 Gstp1 敲除引起的 SHR 血压升高。我们进一步发现,Gstp1 增强了 APLNR 与 Nedd4 E3 泛素连接酶的结合,从而诱导 APLNR 泛素化降解。因此,本研究发现了 Gstp1 在高血压大鼠中的新型抗高血压作用,为设计有效的抗高血压治疗策略提供了实验依据。
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来源期刊
Clinical science
Clinical science 医学-医学:研究与实验
CiteScore
11.40
自引率
0.00%
发文量
189
审稿时长
4-8 weeks
期刊介绍: Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively: Cardiovascular system Cerebrovascular system Gastrointestinal tract and liver Genomic medicine Infection and immunity Inflammation Oncology Metabolism Endocrinology and nutrition Nephrology Circulation Respiratory system Vascular biology Molecular pathology.
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