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.

Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function

“…Pigment epithelium-derived factor (PEDF) could inhibit mTORC1 and induce autophagy in human umbilical vein endothelial cells by activating the P53/Sestrin2 signaling pathway. Silencing P53 or Sestrin2 abrogated the effect of PEDF on endothelial cell autophagy [27]. PEDF also suppressed the inflammatory response of macrophages and stabilized atherosclerotic plaques [28].…”

The role of autophagy in cardiovascular disease: Cross-interference of signaling pathways and underlying therapeutic targets

“…Studies have shown that the knockout of Sesn2 can induce endothelial dysfunction through AMPK dependent pathway and accelerate the formation of LPS induced-myocardial fibrosis ( 111 ), while the over-expression of Sesn2 can activate AMPK to alleviate sepsis induced-myocardial dysfunction ( 112 ). In the umbilical vein endothelial cells, pigment epithelium derived factor (PEDF) induces the expression of p53 and Sesn2, and inhibits mTOR, so as to trigger autophagy ( 113 , 114 ). Other studies have shown that over-expression of Sesn2 triggers mitochondrial autophagy, enhances mitochondrial function, and improves myocardial dysfunction induced by doxorubicin ( 115 ).…”

Sestrin2 in diabetes and diabetic complications

“…A variety of adverse stresses could promote Sestrin2 expression, such as oxidative stress, ER stress, hypoxia, energetic stress, and age-and obesity-associated metabolic pathological conditions (7)(8)(9)(10). Up-regulated Sestrin2 exerts pleiotropic biological effects in diverse physiological and pathological states, through attenuating oxidative stress, and modulating a series of cellular events such as autophagy, ER stress, mitochondrial biogenesis, protein synthesis, cell energy homeostasis and apoptosis, while many of these responsive pathways are interconnected (5,(11)(12)(13)(14).…”