PIASy deficiency mitigates thoracic aortic aneurysm formation via the TGF-β/Smad2/3 pathway.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a common life-threatening cardiovascular disease. Despite advances in clinical management, the underlying molecular mechanisms of TAA formation and develop remain not fully understood. Vascular smooth muscle cells (VSMCs) play a critical role in maintaining aortic wall integrity, and their phenotypic modulation contributes to TAA pathogenesis. Protein inhibitor of activated STAT 4 (PIASy), a transcriptional coregulator, has been implicated in various vascular remodeling processes, but its specific role in VSMCs during TAA progression remains largely unexplored. This study aims to investigate the function of PIASy in TAA and elucidate its potential regulatory effects on VSMC behavior and related signaling pathways. METHODS: PIASy expression levels in human normal and TAA aortic tissues were quantified by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. An in vivo mouse model of TAA was established by angiotensin II (AngII) infusion. Immunohistochemical analyses were conducted to determine PIASy localization in the murine aorta. The in vitro knockdown of PIASy in mouse vascular smooth muscle (MOVAS) cells was performed to assess its biological role. Immunofluorescence staining was used to track rapid changes in VSMC phenotypes. RNA sequencing was employed to identify the downstream pathways regulated by PIASy. RESULTS: PIASy was significantly upregulated in both the human and AngII-induced murine TAA tissues. The in vitro knockdown of PIASy prevented the switching of VSMCs from a contractile phenotype to a secretory phenotype, as evidenced by restored contractile markers and reduced synthetic markers. The transcriptomic analysis showed that transforming growth factor-β (TGF-β) and Smad2/3 act as downstream mediators of PIASy. Mechanistically, PIASy deficiency reversed the AngII-induced suppression of TGF-β and Smad2/3 in VSMCs, thereby maintaining the contractile phenotype. CONCLUSIONS: The loss of PIASy provides protection against TAA by regulating VSMC differentiation via the TGF-β/Smad pathway. Targeting PIASy may represent a promising therapeutic strategy for the prevention and treatment of TAA.