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HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells.

ABSTRACT: An important aspect of vascular biology is the identification of regulators of stress-sensitive genes that play critical roles in mediating inflammatory response. Here, we show that expression of HuR in human umbilical vein endothelial cells is regulated by shear stress and statin treatment; HuR, in turn, regulates other stress-sensitive genes such as Kruppel-like factor 2 (Klf2), endothelial nitric oxide synthase (eNOS), and bone morphogenic protein 4 (BMP-4). We found that siRNA knockdown of HuR-inhibited inflammatory responses in endothelial cells, including ICAM-1 and VCAM-1 up-regulation, NFkappaB phosphorylation, and adhesion of monocytes. Tissue staining of the mouse aorta revealed increased HuR expression in the lesser curvature region of the arch that is exposed to disturbed flow, consistent with our in vitro data. Taken together, these results suggest that HuR plays a critical role in inducing inflammatory response of endothelial cells under mechanical and biochemical stresses.

SUBMITTER: Rhee WJ

PROVIDER: S-EPMC2872448 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells.

Rhee Won Jong WJ Ni Chih-Wen CW Zheng Zhilan Z Chang Kyunghwa K Jo Hanjoong H Bao Gang G

Proceedings of the National Academy of Sciences of the United States of America 20100329 15

An important aspect of vascular biology is the identification of regulators of stress-sensitive genes that play critical roles in mediating inflammatory response. Here, we show that expression of HuR in human umbilical vein endothelial cells is regulated by shear stress and statin treatment; HuR, in turn, regulates other stress-sensitive genes such as Kruppel-like factor 2 (Klf2), endothelial nitric oxide synthase (eNOS), and bone morphogenic protein 4 (BMP-4). We found that siRNA knockdown of H ...[more]

PMID: 20351266

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Project description: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.

Dataset Information

HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells.

Publications

HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells.

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