scholarly journals MiRNA-575 suppresses angiogenesis by targeting Rab5-MEK-ERK pathway in endothelial cells

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Xin Zhao ◽  
Yaping Yi ◽  
Chao Meng ◽  
Ningyuan Fang
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Mitogen Activated Protein Kinase ◽  
Hypertensive Patients ◽  
Downstream Target ◽  
Potential Biomarker ◽  
Mitogen Activated Protein ◽  
Umbilical Vein Endothelial Cells

AbstractHypertension is a major risk factor for the development of atherosclerosis. Increased carotid intima-media thickness (CIMT) is generally considered as an early marker of atherosclerosis. Recently, circulating miRNAs have been implicated both as sensitive biomarkers and key regulators in the development of atherosclerosis. However, the biological functions and molecular regulatory mechanisms for miR-575 on angiogenesis remain unknown. In our study, we first identified up-regulation of circulating miR-575 in plasma of essential hypertensive patients with increased CIMT (iCIMT) compared with those patients with normal CIMT (nCIMT). Furthermore, the overexpression of miR-575 in human umbilical vein endothelial cells (HUVECs) by its mimics significantly inhibited migration and proliferation as well as induction of apoptosis of HUVECs. Inhibition of miR-575 performed the reverse effects of HUVECs. We further suggested Rab5B was the downstream target of miR-575 and knockdown of Rab5B significantly inhibited migration and proliferation of HUVECs. Overexpression of Rab5B largely rescued the miR-575-mediated impairment of angiogenesis processes including: cell proliferation, migration, and apoptosis as well as activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK) signaling. Therefore, our results uncover a novel role of miR-575 in endothelial cells, implying a potential biomarker and clinical target for atherosclerosis in hypertensive patients.

scholarly journals Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3423-3431 ◽  
Author(s):  
Ahmad Salameh ◽  
Federico Galvagni ◽  
Monia Bardelli ◽  
Federico Bussolino ◽  
Salvatore Oliviero
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Capillary Plexus ◽  
Primary Capillary Plexus ◽  
Umbilical Vein Endothelial Cells

AbstractVascular endothelial growth factor receptor-3 (VEGFR-3) plays a key role for the remodeling of the primary capillary plexus in the embryo and contributes to angiogenesis and lymphangiogenesis in the adult. However, VEGFR-3 signal transduction pathways remain to be elucidated. Here we investigated VEGFR-3 signaling in primary human umbilical vein endothelial cells (HUVECs) by the systematic mutation of the tyrosine residues potentially involved in VEGFR-3 signaling and identified the tyrosines critical for its function. Y1068 was shown to be essential for the kinase activity of the receptor. Y1063 signals the receptor-mediated survival by recruiting CRKI/II to the activated receptor, inducing a signaling cascade that, via mitogen-activated protein kinase kinase-4 (MKK4), activates c-Jun N-terminal kinase-1/2 (JNK1/2). Inhibition of JNK1/2 function either by specific peptide inhibitor JNKI1 or by RNA interference (RNAi) demonstrated that activation of JNK1/2 is required for a VEGFR-3–dependent prosurvival signaling. Y1230/Y1231 contributes, together with Y1337, to proliferation, migration, and survival of endothelial cells. Phospho-Y1230/Y1231 directly recruits growth factor receptor–bonus protein (GRB2) to the receptor, inducing the activation of both AKT and extracellular signal–related kinase 1/2 (ERK1/2) signaling. Finally, we observed that Y1063 and Y1230/Y1231 signaling converge to induce c-JUN expression, and RNAi experiments demonstrated that c-JUN is required for growth factor–induced prosurvival signaling in primary endothelial cells.

scholarly journals p38 Mitogen-Activated Protein Kinase Mediates Lipopolysaccharide and Tumor Necrosis Factor Alpha Induction of Shiga Toxin 2 Sensitivity in Human Umbilical Vein Endothelial Cells

2007 ◽  
Vol 76 (3) ◽  
pp. 1115-1121 ◽  
Author(s):  
Matthew K. Stone ◽  
Glynis L. Kolling ◽  
Matthew H. Lindner ◽  
Tom G. Obrig
Keyword(s):  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Umbilical Vein ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Shiga Toxin 2 ◽  
Factor Alpha ◽  
Umbilical Vein Endothelial Cells

ABSTRACTEscherichia coliO157:H7 Shiga toxin 2 (Stx2), one of the causative agents of hemolytic-uremic syndrome, is toxic to endothelial cells, including primary cultured human umbilical vein endothelial cells (HUVEC). This sensitivity of cells to Stx2 can be increased with either lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-α). The goal of the present study was to identify the intracellular signaling pathway(s) by which LPS and TNF-α sensitize HUVEC to the cytotoxic effects of Stx2. To identify these pathways, specific pharmacological inhibitors and small interfering RNAs were tested with cell viability endpoints. A time course and dose response experiment for HUVEC exposure to LPS and TNF-α showed that a relatively short exposure to either agonist was sufficient to sensitize the cells to Stx2 and that both agonists stimulated intracellular signaling pathways within a short time. Cell viability assays indicated that the p38 mitogen-activated protein kinase (MAPK) inhibitors SB202190 and SB203580 and the general protein synthesis inhibitor cycloheximide inhibited both the LPS and TNF-α sensitization of HUVEC to Stx2, while all other inhibitors tested did not inhibit this sensitization. Additionally, SB202190 reduced the cellular globotriaosylceramide content under LPS- and TNF-α-induced conditions. In conclusion, our results show that LPS and TNF-α induction of Stx2 sensitivity in HUVEC is mediated through a pathway that includes p38 MAPK. These results indicate that inhibition of p38 MAPK in endothelial cells may protect a host from the deleterious effects of Stx2.

Anandamide induces apoptosis in human endothelial cells: its regulation system and clinical implications

2003 ◽  
Vol 89 (05) ◽  
pp. 875-884 ◽  
Author(s):  
Kazuyo Yamaji ◽  
Krishna Sarker ◽  
Koichi Kawahara ◽  
Satoshi Iino ◽  
Munekazu Yamakuchi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Crucial Role ◽  
Umbilical Vein ◽  
Mitogen Activated Protein Kinase ◽  
Regulation System ◽  
Dependent Manner ◽  
Vanilloid Receptor 1 ◽  
Mitogen Activated Protein ◽  
Umbilical Vein Endothelial Cells ◽  
Endogenous Cannabinoid

SummaryAnandamide (AEA), an endogenous cannabinoid, is generated by macrophages during shock conditions, and is thought to be a causative mediator of septic shock. Thus, we hypothesized that AEA plays a crucial role in endothelial cell (EC) injury. Here, we demonstrate that AEA induces apoptosis in a time-and dose-dependent manner in human umbilical vein endothelial cells (HUVECs). AEA triggered phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38 mitogen activated protein kinase. AEA also showed a marked increase of interleukin 1β–converting enzyme (ICE)CED-3 family protease (caspase-3) activity. AEA-induced EC death was inhibited by a selective vanilloid receptor 1 (VR1) antagonist, capsazepine, and was enhanced by a VR1 agonist, capsaicin, indicating that AEA induces apoptosis in ECs via VR1. In conclusion, we propose that AEA may play a crucial role in EC injury under conditions of shock, and that the use of inhibitors of the AEA regulation system may have a therapeutic effect under these conditions.

scholarly journals Comparative analysis of the effects of opioids in angiogenesis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tao Feng ◽  
Si Zeng ◽  
Jie Ding ◽  
Gong Chen ◽  
Bin Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Apoptotic Effect ◽  
Toxicity Of Drugs ◽  
Umbilical Vein Endothelial Cells

Abstract Background Angiogenesis, the formation of blood vessel from pre-existing ones, plays an important role in many pathophysiological diseases, such as cancer. Opioids are often used in clinic for the management of chronic pain in cancer patients at terminal phases. Here, we investigated and compared the effects and mechanisms of four opioids on angiogenesis. Methods We performed angiogenesis assays on human umbilical vein endothelial cells (HUVEC) that represent an in vitro model to assess the toxicity of drugs to endothelium. Results Morphine and oxycodone at 0.1 μM to 100 μM dose-dependently increased endothelial cell tube formation and proliferation. We observed the same in endothelial cells exposed to fentanyl at 0.1 μM to 10 μM but there was a gradual loss of stimulation by fentanyl at 100 μM and 1000 μM. Morphine and fentanyl reduced endothelial cell apoptosis-induced by serum withdrawal whereas oxycodone did not display anti-apoptotic effect, via decreasing Bax level. Oxycodone at the same concentrations was less potent than morphine and fentanyl. Different from other three opioids, codeine at all tested concentrations did not affect endothelial cell tube formation, proliferation and survival. Mechanism studies demonstrated that opioids acted on endothelial cells via μ-opioid receptor-independent pathway. Although we observed the increased phosphorylation of mitogen-activated protein kinase (MAPK) in cells exposed to morphine, fentanyl and oxycodone, the rescue studies demonstrated that the stimulatory effects of morphine but not fentanyl nor oxycodone were reversed by a specific MAPK inhibitor. Conclusion Our work demonstrates the differential effects and mechanisms of opioids on angiogenesis.

The Prominent Role of P38 Mitogen-Activated Protein Kinase in Insulin-Mediated Enhancement of VCAM-1 Expression in Endothelial Cells

2007 ◽  
Vol 20 (3) ◽  
pp. 539-555 ◽  
Author(s):  
R. Madonna ◽  
M. Massaro ◽  
A. Pandolfi ◽  
A. Consoli ◽  
R. De Caterina
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Umbilical Vein ◽  
Mitogen Activated Protein Kinase ◽  
Insulin Effect ◽  
Mitogen Activated Protein ◽  
Umbilical Vein Endothelial Cells ◽  
Interfering Rna ◽  
Cell Adhesion Molecule 1

Insulin levels are a marker for cardiovascular events, but the link between hyperinsulinemia and atherosclerosis is poorly understood. We previously showed that insulin increases monocyte-endothelial interactions and the endothelial expression of the pro-atherogenic vascular cell adhesion molecule-1 (VCAM-1). The aim of this study is to examine molecular mechanisms involved in the effect of insulin on VCAM-1 expression. Human umbilical vein endothelial cells (HUVEC) were incubated with insulin (0–24 h) ± inhibitors of signaling pathways potentially involved. At pathophysiological concentrations (10−9-10−7 M), insulin selectively induced VCAM-1 expression. The p38mitogen activated protein(MAP) kinase inhibitors SB203580 and SB202190, and partially the c-Jun NH2-terminal kinase (JNK) inhibitor SP600127, decreased insulin effect on VCAM-1. Gene silencing by small interfering RNA significantly reduced the expression of p38MAP kinase, and this was accompanied by suppression of insulin-stimulated VCAM-1 expression. Treatment with insulin also led to the activation of NF-κB and induction of IκB-α phosphorylation, thus accounting for NF-κB translocation into the nucleus. Co-treatment of HUVEC with insulin and SB202190 strongly reverted the stimulatory effect of insulin on NF-κB activation, thus establishing a link between NF-κB activation and p38MAPkinase-mediated induction of VCAM-1 by insulin. In conclusion, pathophysiological insulin concentrations increase VCAM-1 expression and activate NF-κB. This mostly occurs through stimulation of p38MAP kinase.

Sign in / Sign up

Export Citation Format

Share Document