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21 November 2019 : Laboratory Research  

Tumor Necrosis Factor-alpha (TNF-α) Enhances miR-155-Mediated Endothelial Senescence by Targeting Sirtuin1 (SIRT1)

Qianyun Guo12ABDEFG, Haitong Zhang1BC, Bin Zhang1C, Erli Zhang1ADEFG, Yongjian Wu1AEG*

DOI: 10.12659/MSM.919721

Med Sci Monit 2019; 25:8820-8835


BACKGROUND: Sirtuin1 (SIRT1) participates in a wide variety of cellular processes, but the molecular mechanism remains largely unknown. miR-155 is an element of the inflammatory signaling pathway in atherosclerosis. Therefore, we tested the hypothesis that TNF-α stimulates miR-155 to target SIRT1 and thereby regulates endothelial senescence, and we also explored the function of miR-155 as a regulator of cardiovascular diseases.

MATERIAL AND METHODS: TNF-α was used to stimulate human umbilical vein endothelial cells (HUVECs), after which protein and gene expression were assessed via Western blotting and RT-qPCR. miR-155 targeting of SIRT1 was confirmed via luciferase reporter assays, while MTT and senescence-associated β-galactosidase (SA-β-gal) assays were used for quantifying cellular proliferation and senescence.

RESULTS: We found that miR-155 was upregulated in response to TNF-α treatment, in addition to inducing marked changes in SIRT1/FoxO-1/p21 pathway protein level. When we overexpressed miR-155 mimics, SIRT1 was markedly reduced, whereas miR-155 inhibition had the opposite effect in TNF-α-treated cells. We additionally confirmed that miR-155 was able to directly bind to SIRT1 3’-UTR, and that inhibition of miR-155 reduced the ability of TNF-α to induce senescence in HUVECs, thereby leading to their enhanced proliferation. Simvastatin was associated with suppression of miR-155 expression in HUVECs following TNF-α treatment, and with a corresponding reduction in TNF-α-induced senescence, whereas miR-155 overexpression had the opposite effect.

CONCLUSIONS: Our findings suggest that TNF-α upregulates miR-155, which then targets SIRT1, suppressing its expression and driving HUVEC apoptosis. Simvastatin disrupted this senescence mechanism via the miR-155/SIRT1/FoxO-1/p21 pathway signaling. Hence, miR-155 is a possible therapeutic approach to endothelial senescence in the development of cardiovascular diseases.

Keywords: atherosclerosis, endothelial cells, Sirtuin 1, Cellular Senescence, Human Umbilical Vein Endothelial Cells

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750