1. Academic Validation
  2. Sirtuin 1 ameliorates defenestration in hepatic sinusoidal endothelial cells during liver fibrosis via inhibiting stress-induced premature senescence

Sirtuin 1 ameliorates defenestration in hepatic sinusoidal endothelial cells during liver fibrosis via inhibiting stress-induced premature senescence

  • Cell Prolif. 2021 Mar;54(3):e12991. doi: 10.1111/cpr.12991.
Xiaoying Luo 1 2 Yangqiu Bai 1 Shuli He 1 Suofeng Sun 1 2 Xiaoke Jiang 1 Zhiyu Yang 1 2 Di Lu 1 2 Peiru Wei 1 Yuan Liang 1 Cong Peng 1 Yaru Wang 1 Ruli Sheng 1 Shuangyin Han 1 Xiuling Li 1 Bingyong Zhang 1
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China.
  • 2 Microbiome Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China.
Abstract

Objective: Premature senescence is related to progerin and involves in endothelial dysfunction and liver diseases. Activating Sirtuin 1 (SIRT1) ameliorates liver fibrosis. However, the mechanisms of premature senescence in defenestration of hepatic sinusoidal endothelial cells (HSECs) and how SIRT1 affects HSECs fenestrae remain elusive.

Methods: We employed the CCl4 -induced liver fibrogenesis rat models and cultured primary HSECs in vitro, administered with the SIRT1-adenovirus vector, the activator of SIRT1 and knockdown NOX2. We measured the activity of senescence-associated β-galactosidase (SA-β-gal) in HSECs. Meanwhile, the protein expression of SIRT1, NOX2, progerin, Lamin A/C, Ac p53 K381 and total p53 was detected by Western blot, co-immunoprecipitation and immunofluorescence.

Results: In vivo, premature senescence was triggered by oxidative stress during CCl4 -induced HSECs defenestration and liver fibrogenesis, whereas overexpressing SIRT1 with adenovirus vector lessened premature senescence to relieve CCl4 -induced HSECs defenestration and liver fibrosis. In vitro, HSECs fenestrae disappeared, with emerging progerin-associated premature senescence; these effects were aggravated by H2 O2 . Nevertheless, knockdown of NOX2, activation of SIRT1 with resveratrol and SIRT1-adenovirus vector inhibited progerin-associated premature senescence to maintain fenestrae through deacetylating p53. Furthermore, more Ac p53 K381 and progerin co-localized with the abnormal accumulation of actin filament (F-actin) in the nuclear envelope of H2 O2 -treated HSECs; in contrast, these effects were rescued by overexpressing SIRT1.

Conclusion: SIRT1-mediated deacetylation maintains HSECs fenestrae and attenuates liver fibrogenesis through inhibiting oxidative stress-induced premature senescence.

Keywords

defenestration; hepatic sinusoidal endothelial cell; premature senescence; progerin; sirtuin 1.

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