SIRT1 ameliorates premature senescence-induced defenestration in hepatic sinusoidal endothelial cell

Zhang, B.; Luo, X.; Bai, Y.; He, S.; Jiang, X.; Yang, Z.; Sun, S.; Lu, D.; Wei, P.; Liang, Y.; Peng, C.; Wang, Y.; Sheng, R.; Han, S.; Li, X.

doi:10.1101/2020.04.24.059048

bioRxiv · 10.1101/2020.04.24.059048

SIRT1 ameliorates premature senescence-induced defenestration in hepatic sinusoidal endothelial cell

Zhang, B.·Luo, X.·Bai, Y.·He, S.·Jiang, X.·Yang, Z.·Sun, S.·Lu, D.·Wei, P.·Liang, Y.·Peng, C.·Wang, Y.·Sheng, R.·Han, S.·Li, X.

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Abstract

Premature senescence, linked to progerin, involves in endothelial dysfunction and liver diseases. Activating sirtuin 1 (SIRT1) ameliorates liver fibrosis. However, the potential mechanisms of premature senescence in defenestration in hepatic sinusoidal endothelial cells (HSECs) and how SIRT1 affects fenestrae remains elusive. Our study showed that in vivo, premature senescence occurred, with decrease of SIRT1, during CCl4-induced defenestration in HSECs and liver fibrogenesis; whereas overexpressing SIRT1 with adenovirus vector lessened progerin-associated premature senescence to relieve CCl4-induced defenestration and liver fibrosis. In vitro, fenestrae in HSECs disappeared, with progerin-associated premature senescence; these effects aggravated by H2O2-induced oxidative damage. Nevertheless, knockdown of NOX2 or overexpression of SIRT1 with adenovirus vector reduced progerin-associated premature senescence to maintain fenestrae through deacetylating p53. Furthermore, more Ac p53 K381 and progerin co-localized with accumulation of actin filament (F-actin) in the nuclear envelope of H2O2-treated HSECs; in contrast, these effects were rescued by overexpressing SIRT1. In conclusion, NOX2-dependent oxidative damage aggravates defenestration in HSECs via progerin-associated premature senescence; SIRT1-mediated deacetylation of p53 maintains fenestrae and attenuates liver fibrogenesis through inhibiting premature senescence.

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Zhang, B., Luo, X., Bai, Y., He, S., Jiang, X., Yang, Z., Sun, S., Lu, D., Wei, P., Liang, Y., Peng, C., Wang, Y., Sheng, R., Han, S., Li, X.. 2020-04-24. SIRT1 ameliorates premature senescence-induced defenestration in hepatic sinusoidal endothelial cell. https://doi.org/10.1101/2020.04.24.059048

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