Objectives: WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) orchestrates diverse cellular processes through substrate-specific protein ubiquitination. While its roles in oncogenesis and metabolic regulation are well-characterized, emerging evidence suggests potential involvement in cardiovascular pathophysiology, though its precise functions and regulatory mechanisms in vascular smooth muscle cells (VSMCs) remain undefined. This study aimed to delineate the mechanistic contribution of WWP1 to angiotensin II (Ang II)-mediated hypertensive vasculopathy, with particular focus on VSMCs dysfunction. Methods: We employed an Ang II-induced VSMC model to investigate WWP1 expression and function, utilizing ectopic overexpression techniques to assess its impact on cellular behaviors. Functional analyses, including Transwell assay, cell viability assay (Cell Counting Kit-8), immunofluorescence, and Phalloidin staining assay, were conducted to evaluate WWP1-mediated effects under Ang II stimulation. Mechanistic exploration involved coimmunoprecipitation assays to identify protein-protein interactions between WWP1 and signal transducer and activator of transcription 3 (STAT3) in VSMCs. Results: Our findings revealed 3 key mechanistic insights: (1) Ang II induction triggered significant WWP1 upregulation in VSMCs; (2) WWP1 overexpression exacerbated pathological VSMC behaviors, amplifying Ang II-induced proliferation and migration while promoting synthetic phenotypic transition; and (3) coimmunoprecipitation and colocalization studies identified a novel Ang II-dependent WWP1-STAT3 complex that correlated with vascular lesion severity in hypertensive models. These results collectively establish WWP1 as a master regulator of STAT3-mediated VSMC dysfunction in hypertensive vasculopathy. Conclusion: This work establishes WWP1 as a crucial regulator of hypertensive vasculopathy through STAT3 interaction in VSMCs. Our findings position WWP1 as a novel therapeutic target for vascular remodeling interventions, with mechanistic insights suggesting potential for dual-target strategies combining WWP1 inhibition with STAT3 pathway modulation.
Lu et al. (Sun,) studied this question.