[CDYL deficiency promotes vascular smooth muscle cell phenotypic switching through H3K18 crotonylation-mediated SGK1 transcriptional activation].

To investigate the potential mechanism of histone crotonylation in the phenotypic switching of vascular smooth muscle cells (VSMC) and to identify novel therapeutic targets for the prevention and treatment of aortic dissection and aortic aneurysm. Experimental approaches, including in vitro cellular and molecular biology assays, were employed. The study design was as follows: VSMCs were cultured in vitro and treated with 100 nmol/L angiotensin Ⅱ to induce phenotypic switching. Morphological observation and Western blot analysis were used to examine the expression of phenotypic switching markers and chromodomain Y-like protein (CDYL). Interference and overexpression experiments were performed to assess the role of CDYL in VSMC phenotypic switching and its regulatory effect on histone crotonylation. Quantitative real-time PCR (qRT-PCR) and chromatin immunoprecipitation (ChIP) assays were applied to measure the expression of serum and glucocorticoid-regulated kinase 1 (SGK1) during VSMC phenotypic switching and to analyze the potential mechanism by which CDYL regulates SGK1 expression through H3K18 crotonylation. The results showed that CDYL was significantly downregulated during VSMC phenotypic switching (0.51±0.05,P<0.001) and functionally suppressed this process. Western blot analysis revealed that CDYL negatively regulated the level of H3K18 crotonylation. Compared to the AngII group, CDYL inhibition upregulated H3K18cr (3.14±0.22 vs. 4.24±0.16,P<0.05), whereas CDYL overexpression restored H3K18cr levels (3.14±0.22 vs. 1.76±0.07,P<0.001). Meanwhile, SGK1 was markedly upregulated during VSMC phenotypic switching (3.14±0.18,P<0.001) and was negatively regulated by CDYL. ChIP assays demonstrated that CDYL-mediated H3K18 crotonylation suppressed SGK1 expression. In conclusion, downregulation of CDYL promotes histone H3K18 crotonylation, thereby increasing SGK1 expression and accelerating VSMC phenotypic switching.