Genistein suppresses ox‐LDL‐elicited oxidative stress and senescence in HUVECs through the SIRT1‐p66shc‐Foxo3a pathways

Abstract

The anti-senescence function of genistein is related to inhibiting oxidative stress, however, the mechanism has not been clarified. The present study aimed to explore the effects of genistein on oxidized low-density lipoprotein (ox-LDL)-induced endothelial senescence and the role of the sirtuin-1 (SIRT1)-66-kDa Src homology 2 domain-containing protein (p66Shc)-forkhead box protein O3 (Foxo3a) pathways in the process. In this paper, human umbilical vein endothelial cells were pretreated with 1000 nM genistein for 30 min and then incubated with 50 mg/L ox-LDL for another 12 h; meanwhile, the functions of adenovirus-mediated overexpression of p66shc and small interfering RNA-mediated silencing of SIRT1 were investigated.Results showed that genistein pretreatment alleviated ox-LDL-induced mitochondrial reactive oxygen species, the levels of oxidatively modified DNA (8-OHdG) and pai-1, and the activity of SA-β-gal, which was associated with mitigating p66shc.Further studies indicated the inhibitory effect of genistein on p66shc was correlated with suppressing the acetylation and phosphorylation of p66shc, and ameliorating its mitochondrial translocation by activating SIRT1. Moreover, the inactivated p66shc could enhance the activity of Foxo3a via restraining the phosphorylation and triggering nucleus accumulation. The study demonstrates genistein could prevent ox-LDL-induced mitochondrial oxidative stress and senescence through the SIRT1-p66shc-Foxo3a pathways.

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence

“…Concerning senescence, genistein alleviates the genotoxicity and the cytotoxicity triggered by UVB exposure in human dermal fibroblasts [ 277 ]. Mechanistically, genistein reduces OS-induced senescence by mitigating the levels of mitochondrial ROS and of the DNA oxidation marker 8-OHdG, as well as by upregulating the SIRT1-FOXO3 axis, which is known to prevent aging [ 278 ].…”

Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy

“…Studies have shown that Sirt1 is related to regulating the expression of p66Shc, and the level of p66Shc is reduced in rats with knockout of Sirt1 gene, while the level of p66Shc can be restored by transfection of Sirt1 gene [75]. Sirt1 is a nicotinamide adenine dinucleotide (NAD +) dependent enzyme which can catalyze the deacetylation of lysine residues of histone and participate in the regulation of multiple vital movement such as proliferation, growth and activation [76,77].…”

Ultrasound-targeted microbubble technology facilitates SAHH gene delivery to treat diabetic cardiomyopathy by activating AMPK pathway

“… 7 Ling et al. 8 , 25 , 26 , 27 reported that the DNA methylation of p66shc is regulated by SAHH, with SAHH inhibition inducing endothelial dysfunction; p66shc exerts its effect through both replicative aging and stress-induced premature aging of hepatocytes, endothelial cells, and renal tubular cells. In our experiments, the expression of SAHH was decreased in both in vitro and in vivo DCM models.…”