N-acetylneuraminic acid modulates SQSTM1/p62 sialyation-mediated ubiquitination degradation contributing to vascular endothelium dysfunction in experimental atherosclerosis mice.
Autor: | Chen L; College of Pharmacy, Chongqing Medical University, Chongqing, China.; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China., Qiu H; College of Pharmacy, Chongqing Medical University, Chongqing, China.; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China., Chen Q; College of Pharmacy, Chongqing Medical University, Chongqing, China.; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China., Xiang P; College of Pharmacy, Chongqing Medical University, Chongqing, China.; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China., Lei J; Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University, Xi'an, China., Zhang J; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China., Lu Y; College of Pharmacy, Chongqing Medical University, Chongqing, China.; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China., Wang X; College of Pharmacy, Chongqing Medical University, Chongqing, China.; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China., Wu S; Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China., Yu C; College of Pharmacy, Chongqing Medical University, Chongqing, China.; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China., Ma L; College of Pharmacy, Chongqing Medical University, Chongqing, China.; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China. |
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Jazyk: | angličtina |
Zdroj: | IUBMB life [IUBMB Life] 2024 Mar; Vol. 76 (3), pp. 161-178. Date of Electronic Publication: 2023 Oct 11. |
DOI: | 10.1002/iub.2788 |
Abstrakt: | Sialic acid (SIA) has been reported to be a risk factor for atherosclerosis (AS) due to its high plasma levels in such patients. However, the effect of increasing SIA in circulation on endothelial function during AS progression remains unclear. In the present study, ApoE -/- mice and endothelial cells line (HUVEC cells) were applied to investigate the effect of SIA on AS progression and its potential molecular mechanism. In vivo, mice were injected intraperitoneally with Neu5Ac (main form of SIA) to keep high-level SIA in circulation. ORO, H&E, and Masson staining were applied to detect the plaque progression. In vitro, HUVECs were treated with Neu5Ac at different times, CCK-8, RT-PCR, western blot, and immunoprecipitation methods were used to analyze its effects on endothelial function and the potential involved mechanism. Results from the present study showed that high plasma levels of Neu5Ac in ApoE -/- mice could aggravate the plaque areas as well as increase necrotic core areas and collagen fiber contents. Remarkably, Neu5Ac levels in circulation displayed a positive correlation with AS plaque areas. Furthermore, results from HUVECs showed that Neu5Ac inhibited cells viability in a time/dose-dependent manner, by then induced the activation of inflammation makers such as ICAM-1 and IL-1β. Mechanism study showed that the activation of excessive autophagy medicated by SQSTM1/p62 displayed an important role in endothelium inflammatory injury. Neu5Ac could modify SQSTM1/p62 as a sialylation protein, and then increase its level with ubiquitin binding, further inducing ubiquitination degradation and being involved in the excessive autophagy pathway. Inhibition of sialylation by P-3Fax-Neu5Ac, a sialyltransferase inhibitor, reduced the binding of SQSTM1/p62 to ubiquitin. Together, these findings indicated that Neu5Ac increased SQSTM1/p62-ubiquitin binding through sialylation modification, thereby inducing excessive autophagy and subsequent endothelial injury. Inhibition of SQSTM1/p62 sialylation might be a potential strategy for preventing such disease with high levels of Neu5Ac in circulation. (© 2023 International Union of Biochemistry and Molecular Biology.) |
Databáze: | MEDLINE |
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