20-Hydroxyecdysone inhibits inflammation via SIRT6-mediated NF-κB signaling in endothelial cells
Copyright © 2023. Published by Elsevier B.V..
20-Hydroxyecdysone (20E) is known to have numerous pharmacological activities and can be used to treat diabetes and cardiovascular diseases. However, the protective effects of 20E against endothelial dysfunction and its targets remain unclear. In the present study, we revealed that 20E treatment could modulate the release of the endothelium-derived vasomotor factors NO, PGI2 and ET-1 and suppress the expression of ACE in TNF-α-induced 3D-cultured HUVECs. In addition, 20E suppressed the expression of CD40 and promoted the expression of SIRT6 in TNF-α-induced 3D-cultured HUVECs. The cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular docking results demonstrated that 20E binding increased SIRT6 stability, indicating that 20E directly bound to SIRT6 in HUVECs. Further investigation of the underlying mechanism showed that 20E could upregulate SIRT6 levels and that SIRT6 knockdown abolished the regulatory effect of 20E on CD40 in TNF-α-induced HUVECs, while SIRT6 overexpression further improved the effect of 20E. Moreover, we found that 20E could reduce the acetylation of NF-κB p65 (K310) through SIRT6, but the catalytic inactive mutant SIRT6 (H133Y) did not promote the deacetylation of NF-κB p65, suggesting that the inhibitory effect of 20E on NF-κB p65 was dependent on SIRT6 deacetylase activity. Additionally, our results indicated that 20E inhibited NF-κB via SIRT6, and the expression of CD40 was increased in HUVECs treated with SIRT6 siRNA and NF-κB inhibitor. In conclusion, the present study demonstrates that 20E exerts its effect through SIRT6-mediated deacetylation of NF-κB p65 (K310) to inhibit CD40 expression in ECs, and 20E may have therapeutic potential for the treatment of cardiovascular diseases.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:1870 |
---|---|
Enthalten in: |
Biochimica et biophysica acta. Molecular cell research - 1870(2023), 5 vom: 15. Juni, Seite 119460 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Jin, Zhen [VerfasserIn] |
---|
Links: |
---|
Themen: |
20-Hydroxyecdysone |
---|
Anmerkungen: |
Date Completed 22.05.2023 Date Revised 22.05.2023 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1016/j.bbamcr.2023.119460 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM354636863 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM354636863 | ||
003 | DE-627 | ||
005 | 20231226062638.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1016/j.bbamcr.2023.119460 |2 doi | |
028 | 5 | 2 | |a pubmed24n1182.xml |
035 | |a (DE-627)NLM354636863 | ||
035 | |a (NLM)36958525 | ||
035 | |a (PII)S0167-4889(23)00031-9 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Jin, Zhen |e verfasserin |4 aut | |
245 | 1 | 0 | |a 20-Hydroxyecdysone inhibits inflammation via SIRT6-mediated NF-κB signaling in endothelial cells |
264 | 1 | |c 2023 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 22.05.2023 | ||
500 | |a Date Revised 22.05.2023 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Copyright © 2023. Published by Elsevier B.V. | ||
520 | |a 20-Hydroxyecdysone (20E) is known to have numerous pharmacological activities and can be used to treat diabetes and cardiovascular diseases. However, the protective effects of 20E against endothelial dysfunction and its targets remain unclear. In the present study, we revealed that 20E treatment could modulate the release of the endothelium-derived vasomotor factors NO, PGI2 and ET-1 and suppress the expression of ACE in TNF-α-induced 3D-cultured HUVECs. In addition, 20E suppressed the expression of CD40 and promoted the expression of SIRT6 in TNF-α-induced 3D-cultured HUVECs. The cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular docking results demonstrated that 20E binding increased SIRT6 stability, indicating that 20E directly bound to SIRT6 in HUVECs. Further investigation of the underlying mechanism showed that 20E could upregulate SIRT6 levels and that SIRT6 knockdown abolished the regulatory effect of 20E on CD40 in TNF-α-induced HUVECs, while SIRT6 overexpression further improved the effect of 20E. Moreover, we found that 20E could reduce the acetylation of NF-κB p65 (K310) through SIRT6, but the catalytic inactive mutant SIRT6 (H133Y) did not promote the deacetylation of NF-κB p65, suggesting that the inhibitory effect of 20E on NF-κB p65 was dependent on SIRT6 deacetylase activity. Additionally, our results indicated that 20E inhibited NF-κB via SIRT6, and the expression of CD40 was increased in HUVECs treated with SIRT6 siRNA and NF-κB inhibitor. In conclusion, the present study demonstrates that 20E exerts its effect through SIRT6-mediated deacetylation of NF-κB p65 (K310) to inhibit CD40 expression in ECs, and 20E may have therapeutic potential for the treatment of cardiovascular diseases | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a 20-Hydroxyecdysone | |
650 | 4 | |a 3D culture | |
650 | 4 | |a CD40 | |
650 | 4 | |a NF-κB | |
650 | 4 | |a SIRT6 | |
650 | 7 | |a NF-kappa B |2 NLM | |
650 | 7 | |a Ecdysterone |2 NLM | |
650 | 7 | |a 5289-74-7 |2 NLM | |
650 | 7 | |a Tumor Necrosis Factor-alpha |2 NLM | |
650 | 7 | |a Sirtuins |2 NLM | |
650 | 7 | |a EC 3.5.1.- |2 NLM | |
650 | 7 | |a SIRT6 protein, human |2 NLM | |
650 | 7 | |a EC 3.5.1.- |2 NLM | |
700 | 1 | |a Wang, Bo |e verfasserin |4 aut | |
700 | 1 | |a Ren, Lingxuan |e verfasserin |4 aut | |
700 | 1 | |a Yang, Jianjun |e verfasserin |4 aut | |
700 | 1 | |a Zheng, Zihan |e verfasserin |4 aut | |
700 | 1 | |a Yao, Feng |e verfasserin |4 aut | |
700 | 1 | |a Ding, Rongcheng |e verfasserin |4 aut | |
700 | 1 | |a Wang, Jianjiang |e verfasserin |4 aut | |
700 | 1 | |a He, Jianyu |e verfasserin |4 aut | |
700 | 1 | |a Wang, Weirong |e verfasserin |4 aut | |
700 | 1 | |a Nan, Guanjun |e verfasserin |4 aut | |
700 | 1 | |a Lin, Rong |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Biochimica et biophysica acta. Molecular cell research |d 2017 |g 1870(2023), 5 vom: 15. Juni, Seite 119460 |w (DE-627)NLM264216326 |x 1879-2596 |7 nnns |
773 | 1 | 8 | |g volume:1870 |g year:2023 |g number:5 |g day:15 |g month:06 |g pages:119460 |
856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bbamcr.2023.119460 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 1870 |j 2023 |e 5 |b 15 |c 06 |h 119460 |