WWP2 regulates SIRT1‐STAT3 acetylation and phosphorylation involved in hypertensive angiopathy

Abstract 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.