WWP2 is a HECT‐type E3 ubiquitin ligase that regulates various physiological and pathological activities by binding to different substrates, but its function and regulatory mechanism in vascular smooth muscle cells (VSMCs) are still unknown. Here, we clarified the role of WWP2 in the regulation of SIRT1‐STAT3 and the impact of this regulatory process in VSMCs. We demonstrated that WWP2 expression was significantly increased in angiotensin II‐induced VSMCs model. Knockdown of WWP2 significantly inhibited angiotensin II‐induced VSMCs proliferation, migration and phenotypic transformation, whereas overexpression of WWP2 had opposite effects. In vivo experiments showed that vascular smooth muscle‐specific WWP2 knockout mice significantly relieved angiotensin II‐induced hypertensive angiopathy. Mechanistically, mass spectrometry and co‐immunoprecipitation assays identified that WWP2 is a novel interacting protein of SIRT1 and STAT3. Moreover, WWP2 formed a complex with SIRT1‐STAT3, inhibiting the interaction between SIRT1 and STAT3, then reducing the inhibitory effect of SIRT1 on STAT3, ensuing promoting STAT3‐K685 acetylation and STAT3‐Y705 phosphorylation in angiotensin II‐induced VSMCs and mice. In conclusion, WWP2 modulates hypertensive angiopathy by regulating SIRT1‐STAT3 and WWP2 suppression in VSMCs can alleviate hypertensive angiopathy vitro and vivo. These findings provide new insights into the treatment of hypertensive vascular diseases.

中文翻译：

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WWP2调节与高血压性血管病有关的SIRT1-STAT3乙酰化和磷酸化。

WWP2是一种HECT型E3泛素连接酶，通过与不同的底物结合来调节各种生理和病理活动，但是其在血管平滑肌细胞（VSMC）中的功能和调节机制仍然未知。在这里，我们阐明了WWP2在SIRT1-STAT3调节中的作用以及该调节过程对VSMC的影响。我们证明，在血管紧张素II诱导的VSMC模型中，WWP2表达显着增加。抑制WWP2可以显着抑制血管紧张素II诱导的VSMC增殖，迁移和表型转化，而过表达WWP2具有相反的作用。体内实验表明，血管平滑肌特异性WWP2敲除小鼠可明显缓解血管紧张素II引起的高血压血管病。机械上，质谱和免疫共沉淀测定法确定WWP2是SIRT1和STAT3的新型相互作用蛋白。此外，WWP2与SIRT1-STAT3形成复合物，抑制SIRT1与STAT3之间的相互作用，然后降低SIRT1对STAT3的抑制作用，从而在血管紧张素II诱导的VSMC和小鼠中促进STAT3-K685乙酰化和STAT3-Y705磷酸化。总之，WWP2通过调节SIRT1-STAT3调节高血压性血管病，而抑制VSMC中的WWP2可减轻体内和体外的高血压性血管病。这些发现为高血压血管疾病的治疗提供了新的见识。然后降低SIRT1对STAT3的抑制作用，从而促进血管紧张素II诱导的VSMC和小鼠中STAT3-K685乙酰化和STAT3-Y705磷酸化。总之，WWP2通过调节SIRT1-STAT3调节高血压性血管病，而抑制VSMC中的WWP2可以减轻体内和体外的高血压性血管病。这些发现为高血压血管疾病的治疗提供了新的见解。然后降低SIRT1对STAT3的抑制作用，从而在血管紧张素II诱导的VSMC和小鼠中促进STAT3-K685乙酰化和STAT3-Y705磷酸化。总之，WWP2通过调节SIRT1-STAT3调节高血压性血管病，而抑制VSMC中的WWP2可减轻体内和体外的高血压性血管病。这些发现为高血压血管疾病的治疗提供了新的见解。