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作者

Shuai Leng, Haijie Li, Pengfei Zhang, Zhiqiao Dang, Baowei Shao, Shishan Xue, Yansong Ning, Xilong Teng, Leilei Zhang, Honglu Wang, Na Li, Fengquan Zhang, Wenqian Yu

作者单位

Affiliations ¹ Department of Cardiac Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, China. (S.L., H.L., P.Z., Z.D., B.S., S.X., Y.N., X.T., L.Z., H.W., N.L., F.Z., W.Y.). ² Research Center of Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China. (S.L., W.Y.).

刊名

Arteriosclerosis, thrombosis, and vascular biology

年份

2024

ISSN

1524-4636

关键词

dissection, thoracic aorta mass spectrometry sequence analysis, RNA sirtuins ubiquitination.

摘要

Background: The occurrence of thoracic aortic dissection is closely related to the transformation of vascular smooth muscle cells from a contractile to a synthetic phenotype. The role of SGK1 in VSMC phenotypic transformation and TAD occurrence is unclear. Methods: Four-week-old male Sgk1 and Sgk1;Tagln mice were administered β-aminopropionitrile monofumarate for 4 weeks to model TAD. The SGK1 inhibitor GSK650394 was administered daily via intraperitoneal injection to treat the mouse model ...更多

Background: The occurrence of thoracic aortic dissection is closely related to the transformation of vascular smooth muscle cells from a contractile to a synthetic phenotype. The role of SGK1 in VSMC phenotypic transformation and TAD occurrence is unclear. Methods: Four-week-old male Sgk1 and Sgk1;Tagln mice were administered β-aminopropionitrile monofumarate for 4 weeks to model TAD. The SGK1 inhibitor GSK650394 was administered daily via intraperitoneal injection to treat the mouse model of TAD. Immunopurification and mass spectrometry were used to identify proteins that interact with SGK1. Immunoprecipitation, immunofluorescence colocalization, and GST pull-down were used to detect molecular interactions between SGK1 and SIRT6 . RNA-sequencing analysis was performed to evaluate changes in the SIRT6 transcriptome. Quantitative chromatin immunoprecipitation was used to determine the target genes regulated by SIRT6. Functional experiments were also conducted to investigate the role of SGK1-SIRT6-MMP9 in VSMC phenotypic transformation. The effect of SGK1 regulation on target genes was evaluated in human and mouse TAD samples. Results: Sgk1;Tagln or pharmacological blockade of Sgk1 inhibited the formation and rupture of β-aminopropionitrile monofumarate-induced TADs in mice and reduced the degradation of the ECM in vessels. Mechanistically, SGK1 promoted the ubiquitination and degradation of SIRT6 by phosphorylating SIRT6 at Ser338, thereby reducing the expression of the SIRT6 protein. Furthermore, SIRT6 transcriptionally inhibits the expression of MMP9 through epigenetic modification, forming the SGK1-SIRT6-MMP9 regulatory axis, which participates in the ECM signaling pathway. Additionally, our data showed that the lack of SGK1-mediated inhibition of ECM degradation and VSMC phenotypic transformation is partially dependent on the regulatory effect of SIRT6-MMP9. Conclusions: These findings highlight the key role of SGK1 in the pathogenesis of TAD. A lack of SGK1 inhibits VSMC phenotypic transformation by regulating the SIRT6-MMP9 axis, providing insights into potential epigenetic strategies for TAD treatment.收起

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