YTHDF3 Hinders the Proliferation of Ang II-Induced Vascular Smooth Muscle Cells While Promoting Apoptosis and Inflammation in Abdominal Aortic Aneurysm via SIRT2/FOXO1

BACKGROUND AND OBJECTIVES: This study investigates the diagnostic value of YTHDF3 for abdominal aortic aneurysm (AAA) and further determines its regulatory mechanism in angiotensin II (Ang II)-induced vascular smooth muscle cells (VSMCs). METHODS: YTHDF3 expression in abdominal aortic tissues and adjacent non-aneurysm aortic tissues of AAA patients was tested via reverse transcription-quantitative polymerase chain reaction and Western blot. The diagnostic value of YTHDF3 protein expression for AAA was evaluated by receiver operating characteristic curve. VSMCs were stimulated by Ang II in vitro and transfected with sh-YTHDF3. Cell proliferation was assessed via 5-ethynyl-2'-deoxyuridine and cell counting kit-8 assays. Apoptosis was measured via caspase-3/9 activity and TUNEL assays. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels were detected via enzyme-linked immunosorbent assay. The regulatory mechanism of YTHDF3/sirtuin 2 (SIRT2)/FOXO1 was determined via methylated RNA immunoprecipitation-qPCR, RNA immunoprecipitation, actinomycin D treatment, cycloheximide, and co-immunoprecipitation. RESULTS: YTHDF3 is highly expressed in AAA tissues and positively correlated with AAA diameter, TNF-α, IL-1-β, and IL-6 levels. YTHDF3 has certain diagnostic value for AAA. Knockdown of YTHDF3 alleviates the inhibitory effect of Ang II on VSMC proliferation, as well as its promoting effect on apoptosis and inflammation. Mechanistically, N6 methyladenosine reader YTHDF3 directly binds to SIRT2 mRNA and maintains its stability, facilitates the deacetylation of FOXO1, and reduces the stability of FOXO1 protein. CONCLUSIONS: YTHDF3 is highly expressed in AAA tissues and Ang II-induced VSMCs. YTHDF3 hinders the proliferation of Ang II-induced VSMCs while promoting apoptosis and inflammation. YTHDF3 deficiency exerts protective effect by interfering with SIRT2/FOXO1 axis.