PMID- 24561862
OWN - NLM
STAT- MEDLINE
DCOM- 20140615
LR  - 20200930
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 306
IP  - 8
DP  - 2014 Apr 15
TI  - Inhibition of endocytosis exacerbates TNF-alpha-induced endothelial dysfunction via 
      enhanced JNK and p38 activation.
PG  - H1154-63
LID - 10.1152/ajpheart.00885.2013 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine that causes 
      endothelial dysfunction. Endocytosis of TNF-alpha receptors (TNFR) precedes endosomal 
      reactive oxygen species (ROS) production, which is required for NF-kappaB activation 
      in vascular smooth muscle cells. It is unknown how endocytosis of TNFRs impacts 
      signaling in endothelial cells. We hypothesized that TNF-alpha-induced endothelial 
      dysfunction is induced by both endosomal and cell surface events, including NF-kappaB 
      and mitogen-activated protein kinases (MAPKs) activation, and endocytosis of the 
      TNFR modifies signaling. Mesenteric artery segments from C57BL/6 mice were 
      treated with TNF-alpha (10 ng/ml) for 22 h in tissue culture, with or without 
      signaling inhibitors (dynasore for endocytosis, SP600125 for JNK, SB203580 for 
      p38, U0126 for ERK), and vascular function was assessed. Endothelium-dependent 
      relaxation to acetylcholine (ACh) was impaired by TNF-alpha, and dynasore exacerbated 
      this, whereas JNK or p38 inhibition prevented these effects. In cultured 
      endothelial cells from murine mesenteric arteries, dynasore potentiated JNK and 
      p38 but not ERK phosphorylation and promoted cell death. NF-kappaB activation by 
      TNF-alpha was decreased by dynasore. JNK inhibition dramatically increased both the 
      magnitude and duration of TNF-alpha-induced NF-kappaB activation and potentiated 
      intercellular adhesion molecule-1 (ICAM-1) activation. Dynasore still inhibited 
      NF-kappaB activation in the presence of SP600125. Thus TNF-alpha-induced endothelial 
      dysfunction is both JNK and p38 dependent. Endocytosis modulates the balance of 
      NF-kappaB and MAPK signaling, and inhibition of NF-kappaB activation by JNK limits this 
      pro-proliferative signal, which may contribute to endothelial cell death in 
      response to TNF-alpha.
FAU - Choi, Hyehun
AU  - Choi H
AD  - Department of Pediatrics, Vanderbilt University Medical Center, Nashville, 
      Tennessee.
FAU - Nguyen, Hong N
AU  - Nguyen HN
FAU - Lamb, Fred S
AU  - Lamb FS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140221
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Hydrazones)
RN  - 0 (N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide)
RN  - 0 (NF-kappa B)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Proliferation
MH  - Cell Survival
MH  - Endocytosis/drug effects/*physiology
MH  - Endothelial Cells/*physiology
MH  - Enzyme Activation/drug effects
MH  - Hydrazones/pharmacology
MH  - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/*physiology
MH  - Male
MH  - Mesenteric Arteries
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/physiology
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Receptors, Tumor Necrosis Factor/metabolism
MH  - Signal Transduction/physiology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*physiology
OTO - NOTNLM
OT  - JNK
OT  - NF-kappaB
OT  - endocytosis
OT  - endothelial dysfunction
OT  - p38 kinase
OT  - tumor necrosis factor-alpha
EDAT- 2014/02/25 06:00
MHDA- 2014/06/16 06:00
CRDT- 2014/02/25 06:00
PHST- 2014/02/25 06:00 [entrez]
PHST- 2014/02/25 06:00 [pubmed]
PHST- 2014/06/16 06:00 [medline]
AID - ajpheart.00885.2013 [pii]
AID - 10.1152/ajpheart.00885.2013 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2014 Apr 15;306(8):H1154-63. doi: 
      10.1152/ajpheart.00885.2013. Epub 2014 Feb 21.