17β-estradiol inhibits H2O2-induced senescence in HUVEC cells through upregulating SIRT3 expression and promoting autophagy

Liu

Front. Cardiovasc. Med.

et al. 2022

The aging of endothelial cells plays a critical role in the development of age-related vascular disease. We established a model of endothelial premature senescence by application of Advanced oxidation protein products (AOPPs) modified bovine serum albumin (AOPP-BSA) in human umbilical vein endothelial cells (HUVECs). This cellular senescence was accompanied with endothelial barrier dysfunction and angiogenesis impairment. It was further revealed that these senescent HUVECs underwent apoptosis evasion and the receptor for advanced glycation endproducts (RAGE) played a role in these processes. The AOPP-induced senescence was regulated by the state of autophagy in HUVECs. We further proved that AOPP-BSA attenuated the autophagy of HUVECs, led to p53 SUMOylation at K386, resulting in endothelial senescence. We also established the animal model of vascular senescence by using ApoE−/− mice fed with high-fat diet plus daily injection of AOPP-BSA to verify the role of p53 SUMOylation in vascular senescence. Combined with intraperitoneal injection of rapamycin, the effect of autophagy on AOPP-induced p53 SUMOylation was also confirmed in vivo. Our data indicates that p53 SUMOylation at K386 plays an important role in AOPP-induced endothelial senescence and apoptosis evasion, suggesting that p53 K386 SUMOylation may serve as a potential therapeutic target in protecting against vascular senescence.

Section: Discussionmentioning

confidence: 99%

p53 SUMOylation Mediates AOPP-Induced Endothelial Senescence and Apoptosis Evasion

Liu

Front. Cardiovasc. Med.

et al. 2022

“…Autophagy can be triggered by different stress stimuli, and cellular outcomes following autophagy induction in ECs vary depending on the nature of the stimulus and specific experimental settings (13,14). Here, we found that autophagy activated by H 2 S reduced Ox-LDLinduced HUVEC apoptosis and that H 2 S induced a beneficial autophagic process to protect ECs.…”

mentioning

confidence: 70%

“…In contrast, exogenous H 2 S promotes mitophagy to protect rat aortic ECs against apoptosis under conditions of high glucose and palmitate levels (11,12). Different stimuli and experimental environments that induce autophagy in ECs have different cellular outcomes (9,13,14). H 2 S inhibits or promotes autophagy through different mechanisms in different cell and animal models, such as by alleviating kidney injury in rats by inhibiting autophagy via regulation of NO production (12), alleviating obstructive nephropathy in mice via inhibition of reactive oxidative stress (ROS)adenosine monophosphate activated protein kinase (AMPK)-mediated autophagy (15).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of hydrogen sulfide on endothelial cells through Sirt1-FoxO1-mediated autophagy

Zhu

et al. 2020

Ann Transl Med

Background: As a new member of the vasculoprotective gasotransmitter family, hydrogen sulfide (H 2 S) functions similar to nitric oxide (NO) and carbon monoxide (CO). Endothelial cell (EC) death and autophagy enable cells to cope with the progression of cardiovascular diseases. However, the impacts and underlying mechanisms of H 2 S in the autophagic process in ECs are not completely understood. Here, we investigated the effects of H 2 S on autophagy in human vascular ECs.Methods: Human umbilical vein endothelial cells (HUVECs) were exposed to different concentrations (0, 50, 100, 200, 500 and 1,000 μmol/L) GYY4137 (H 2 S donor) for indicated times (0, 0.5, 1, 2, 4 and 8 h), with or without pre-treatment with the autophagy inhibitor 3-methyladenine (3-MA) or bafilomycin A1.HUVECs were transfected with sirtuin 1 (Sirt1) overexpression plasmids (PIRES-Sirt1), Sirt1-siRNAs or forkhead box O1 (FoxO1)-siRNA using Lipofectamine 2000. Cell autophagy was evaluated via Western blotting and fluorescence microscopy. Co-immunoprecipitation assay was used to measure acetylation level of FoxO1. The distribution of FoxO1 in the cytoplasm and nucleus was observed using Western blotting and immunofluorescence. Western blotting, flow cytometric analysis, and cell count kit-8 assay were conducted to evaluate the effect of H 2 S on the oxidized low-density lipoprotein (Ox-LDL) induced apoptosis of HUVECs.Results: Using both gain-and loss-of-function experiments, we showed that Sirt1-dependent activation of FoxO1, including its nuclear translocation and deacetylation, was critical for mediating H 2 S-induced autophagy in ECs. Furthermore, H 2 S-induced autophagy protected ECs from Ox-LDL-induced apoptosis by activating Sirt1.Conclusions: These results suggest that Sirt1-mediated autophagy in ECs is a novel mechanism by which H 2 S exerts vascular-protective actions.

“…Once activated, CCND3 binds to activate CDKs, which then phosphorylate a series of proteins to release E2F transcription factors that promote the progression from the G 0 /G 1 phase to the S phase ( 38 – 40 ). Previous studies have reported that CCND3 expression levels were upregulated in breast cancer ( 39 , 41 ) and osteosarcoma ( 42 ). The upregulated expression levels of CCND3 were associated with a poor prognosis in gastric cancer via accelerating cell cycle function ( 43 ).…”

Section: Discussionmentioning

confidence: 98%

miR‑138‑5p suppresses glioblastoma cell viability and leads to cell cycle arrest by targeting cyclin D3

Wu¹,

Wang

Liu

et al. 2020

Oncol Lett

Although malignant glioblastoma (GBM) treatment has significantly improved in the past few decades, the prognosis of GBM remains unsatisfactory. MicroRNA (miR)-138-5p has been reported as a tumor suppressor in several types of human cancer; however, little is known about the function of miR-138-5p in GBM. The present study aimed to investigate the role of miR-138-5p in GBM as well as the underlying molecular mechanisms. The present study performed bioinformatics analysis, reverse transcription-quantitative (RT-q)PCR, western blotting, cell viability assays, colony formation assays, invasion assays and cell cycle analysis to investigate the biological function of miR-138-5p in both patient tissues and cell lines. In addition, miR-138-5p targets in GBM were predicted using Gene Expression Omnibus website and further validated by a dual luciferase reporter gene assay. The results revealed that miR-138-5p expression levels in patients with GBM from a Gene Expression Omnibus dataset were significantly downregulated. RT-qPCR analysis of miR-138-5p expression levels also revealed similar results in GBM tissues and cell lines. The upregulation of miR-138-5p expression levels using a mimic significantly inhibited the cell viability, colony formation and the G 0 /G 1 to S progression in GBM cell lines, suggesting that miR-138-5p may be a tumor suppressor. Moreover, miR-138-5p was discovered to directly target cyclin D3 (CCND3), a protein that serves an important role in the cell cycle, and inhibited its expression. Finally, silencing CCND3 using small interfering RNA suppressed the viability of GBM cells. In conclusion, the results of the present study suggested that miR-138-5p may function as a tumor suppressor in GBM by targeting CCND3, indicating that miR-138-5p may be a novel therapeutic target for patients with GBM.