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P53 mediates PEDF?induced autophagy in human umbilical vein endothelial cells through sestrin2 signaling.

ABSTRACT: Autophagy is a conserved catabolic process by which cytoplasmic components are delivered into lysosomes for degradation. Pigment epithelium?derived factor (PEDF) has been reported to be associated with autophagy and can induce p53 expression; however, the mechanism relating PEDF with autophagy in endothelial cells remains poorly understood. The present study aimed to investigate the association between the PEDF?p53?sestrin pathway and autophagy in human umbilical vein endothelial cells (HUVECs). PEDF?induced autophagy was examined by fluorescence microscopy and western blot analysis. p53 small interfering (si)RNA and sestrin2 siRNA were constructed and transfected into HUVECs prior to PEDF treatment. The protein expression levels of microtubule?associated protein light chain 3 (LC3) I, LC3 II and p62 were evaluated by western blot analysis, and the mRNA expression levels of p53 and sestrin2 were determined using reverse transcription?quantitative polymerase chain reaction analysis. The regulation of mechanistic target of rapamycin (mTOR) was reflected by p70S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E?binding protein 1 (4E?BP1) protein expression levels, as determined by western blot analysis. PEDF could induce HUVEC autophagy by sequentially inducing p53 and sestrin2 expression, as observed by fluorescence microscopy and western blot analysis. Conversely, the induction of sestrin2 by PEDF was eliminated by p53 siRNA. In addition, p53 siRNA and sestrin2 siRNA could attenuate PEDF?induced HUVEC autophagy. Inhibition of mTOR may be the mechanism responsible for PEDF?induced autophagy; as p70S6K and 4E?BP1 phosphorylation levels were significantly upregulated in p53 siRNA?treated and sestrin2 siRNA?treated groups. The findings of the present study indicated that PEDF may trigger autophagy in HUVECs by inducing p53 and sestrin2 expression, and inhibiting mTOR expression; these findings may contribute to the improved understanding of diseases, including cancer and atherosclerosis.

SUBMITTER: Chen T

PROVIDER: S-EPMC6625384 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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p53 mediates PEDF‑induced autophagy in human umbilical vein endothelial cells through sestrin2 signaling.

Chen Tiangui T Li Tianbo T Wang Jiangning J

Molecular medicine reports 20190603 2

Autophagy is a conserved catabolic process by which cytoplasmic components are delivered into lysosomes for degradation. Pigment epithelium‑derived factor (PEDF) has been reported to be associated with autophagy and can induce p53 expression; however, the mechanism relating PEDF with autophagy in endothelial cells remains poorly understood. The present study aimed to investigate the association between the PEDF‑p53‑sestrin pathway and autophagy in human umbilical vein endothelial cells (HUVECs). ...[more]

PMID: 31173218

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Project description:The increasing burden of diabetes in low and middle?income countries is attributable to both genetic and epigenetic factors. Environmental? and lifestyle?associated changes are also considered to be important contributors to this disease. The resultant co?morbidities arising from micro?and macrovascular changes in diabetes are difficult to manage and are an economic burden. However, very little is known about the molecular mechanisms that drive this phenotype. The present study aimed to investigate the role of sirtuin 1 (SIRT1)? and transcription box?3 (TBX?3)?mediated regulation of endothelial dysfunction, given the significance of SIRT1 in glucose metabolism and the role of TBX?3 in the maintenance of cellular proliferation, senescence and apoptosis. Following the recruitment of adult patients with and without diabetes, both SIRT1 and TBX?3 expression was confirmed to be present in the sera of the patients with diabetes and the patients without diabetes; however, both SIRT1 and TBX?3 expression levels were higher in the sera of the patients with diabetes. Human umbilical vein endothelial cells (HUVECs) were further used for in vitro studies. Using TBX?3 and SIRT1 knockdown models, the cellular responses to proliferation, migration, invasion and tube formation were investigated using an MTS, cell cycle analysis, wound healing, Transwell and tube formation assay, respectively. Western blotting was also used to determine the downstream signaling pathways involved. The genetic knockdown of TBX?3 in hyperglycemic conditions significantly decreased the cellular proliferation, migration, invasion and angiogenesis of HUVECs. It was subsequently identified that TBX?3 mediated its effects through the activation of AKT and vascular endothelial growth factor (VEGF) signaling. However, the genetic knockdown of SIRT1 in the presence of TBX?3 overexpression and glucose failed to activate the AKT and VEGF signaling pathways. In conclusion, the results of the present study suggested that SIRT1 may positively regulate TBX?3 in endothelial cells, therefore, SIRT1 and/or TBX?3 may serve as potential novel biomarkers for disease progression.

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P53 mediates PEDF?induced autophagy in human umbilical vein endothelial cells through sestrin2 signaling.

Publications

p53 mediates PEDF‑induced autophagy in human umbilical vein endothelial cells through sestrin2 signaling.

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