Background

Hypertension is a life-threatening disease mainly featured as vascular endothelial dysfunction. This study aims to explore the regulatory role of murine double minute 2 (MDM2) in hypertension and vascular damage.

Methods

Mice were infused with angiotensin II (AngII) to establish a hypertension mouse model in vivo and AngII-stimulated HUVECs were constructed to simulate the damage of vascular endothelial cells in hypertension in vitro. The plasmids targeting to MDM2 was injected to mice or transfected to HUVECs. qRT-PCR and western blot were performed to detect corresponding gene expression in mice aorta. Blood pressure was measured. H&E and Masson staining were conducted to evaluate histological changes of aorta. Responses to the acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in aorta. ZO-1 expression and cell apoptosis were detected by immunofluorescence and TUNEL, respectively. Network formation ability was determined employing a tube formation.

Results

MDM2 was upregulated in hypertensive mice. Knockdown of MDM2 inhibited AngII-induced high BP, histological damage, vascular relaxation to Ach, and promoted the levels of p-eNOS and ZO-1 in the aorta in hypertensive mice. MDM2 knockdown inactivated Notch1 signaling and NLRP3 inflammasome, while the inhibitory effect of MDM2 knockdown on NLRP3 inflammasome activation was partly restored by the activation of Notch1. Furthermore, knockdown of MDM2 relieved AngII-induced endothelial dysfunction in HUVECs, as well as suppressing AngII-promoted cell apoptosis. Whereas, the impacts generated by MDM2 knockdown were partly weakened by the activation of Notch1 signaling or NLRP3 inflammasome.

Conclusion

In summary, knockdown of MDM2 can attenuate vascular endothelial dysfunction in hypertension, which may be achieved through inhibiting the activation of Notch1 and NLRP3 inflammasome.

中文翻译：

---

MDM2 的干扰部分通过阻断 Notch1/NLRP3 炎症小体途径减轻高血压血管内皮功能障碍

背景

高血压是一种以血管内皮功能障碍为主要特征的危及生命的疾病。本研究旨在探讨小鼠双分钟2（MDM2）在高血压和血管损伤中的调节作用。

方法

通过给小鼠输注血管紧张素II（AngII）在体内建立高血压小鼠模型，并构建AngII刺激的HUVEC来模拟体外高血压时血管内皮细胞的损伤。将靶向 MDM2 的质粒注射到小鼠体内或转染到 HUVEC 中。采用qRT-PCR和western blot检测小鼠主动脉中相应基因的表达。测量血压。采用H&E和Masson染色评价主动脉的组织学变化。评估主动脉对乙酰胆碱 (ACh) 和硝普钠 (SNP) 的反应。免疫荧光和TUNEL分别检测ZO-1表达和细胞凋亡。使用管形成来确定网络形成能力。

结果

MDM2 在高血压小鼠中表达上调。敲低 MDM2 可抑制 AngII 诱导的高血压、组织学损伤、Ach 血管舒张，并提高高血压小鼠主动脉中 p-eNOS 和 ZO-1 的水平。MDM2敲低使Notch1信号传导和NLRP3炎症小体失活，而MDM2敲低对NLRP3炎症小体激活的抑制作用通过Notch1的激活而部分恢复。此外，MDM2 的敲低可缓解 AngII 诱导的 HUVEC 内皮功能障碍，并抑制 AngII 促进的细胞凋亡。然而，Notch1 信号传导或 NLRP3 炎症小体的激活部分削弱了 MDM2 敲低产生的影响。

结论

总之，敲低MDM2可以减轻高血压时的血管内皮功能障碍，这可能是通过抑制Notch1和NLRP3炎性体的激活来实现的。