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.
摘要：
高血压是全球疾病负担的主要危险因素。血管收缩和重塑有助于高血压的发展。谷胱甘肽S-转移酶P1（Gstp1）在正常细胞和肿瘤细胞中起着重要的作用。在这项研究中,我们研究了Gstp1对高血压和血管平滑肌细胞（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，高血压大鼠的动脉和VSMC中Gstp1的水平更高。然后，我们在大鼠中开发了腺相关病毒9（AAV9）介导的Gstp1下调和过表达，并通过使用尾套和颈动脉导管方法测量了大鼠的血压。我们发现，自发性高血压大鼠（SHR）和2肾1夹（2K1C）肾血管性高血压大鼠的血压随Gstp1下调而显着升高，而在Gstp1过表达后则明显降低。Gstp1不影响血压正常的Wistar-Kyoto（WKY）大鼠和Sprague-Dawley（SD）大鼠的血压。进一步的体外研究表明，SHR-VSMC中Gstp1敲低可促进细胞增殖，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-VSMC的作用。APLNR拮抗剂F13A可以逆转Gstp1敲低引起的SHR血压升高。我们进一步发现，Gstp1增强APLNR和Nedd4E3泛素连接酶之间的关联，以诱导APLNR泛素化降解。因此，在本研究中，我们发现了Gstp1在高血压大鼠中的新的抗高血压作用,为设计有效的抗高血压治疗策略提供了实验基础.
