Endothelial Nitric Oxide Synthase Activation by Tumor Necrosis Factor Alpha Through Neutral Sphingomyelinase 2, Sphingosine Kinase 1, and Sphingosine 1 Phosphate Receptors: a Novel Pathway Relevant to the Pathophysiology of Endothelium.
From: Department of Pharmaco-Biology, University of Calabria, Rende, Italy.
Arteriosclerosis, thrombosis, and vascular biology
- Publish Date: Jan 2006
- ISSN: 1524-4636
- Volume: 26
- Issue: 1
- Pages: 99-105
- Medium: Internet
- Language: English
- Citation (JAMA): De Palma Clara, Meacci Elisabetta, Perrotta Cristiana, et al. Endothelial Nitric Oxide Synthase Activation by Tumor Necrosis Factor Alpha Through Neutral Sphingomyelinase 2, Sphingosine Kinase 1, and Sphingosine 1 Phosphate Receptors: a Novel Pathway Relevant to the Pathophysiology of Endothelium.. Arterioscler. Thromb. Vasc. Biol. Jan 2006;26:99-105
Abstract
OBJECTIVE: Tumor necrosis factor alpha (TNF-alpha), a key proinflammatory cytokine acting on the endothelium, activates endothelial nitric oxide synthase (eNOS). We have examined the signaling pathway leading to this activation and its biological role in endothelium, which are still unknown. METHODS AND RESULTS: In human endothelial cells, we found that eNOS activation by TNF-alpha is time dependent and requires activation of Akt, a known eNOS activator. eNOS activation was preceded by sequential activation of neutral-sphingomyelinase-2 (N-SMase2) and sphingosine-kinase-1 (SK1) and generation of sphingosine-1-phosphate (Sph1P). Inhibition of N-SMase2 inhibited Sph1P formation, whereas inhibition of SK1 did not affect N-SMase2 activation by TNF-alpha. Blockade of N-SMase2, SK1, or the Sph1P receptors S1P1 and S1P3, either by silencing or pharmacological inhibitors, prevented eNOS activation. Thus, eNOS is activated by TNF-alpha via S1P receptors, activated by Sph1P generated through N-SMase2 and SK1 activation. We found that nitric oxide generated through this pathway has a biological role, because it inhibits the expression of E-selectin and the adhesion of dendritic cells to the endothelium stimulated by TNF-alpha. CONCLUSIONS: This study establishes a previously undescribed link among TNF-alpha, Sph1P, and eNOS in a same signaling pathway of biological relevance in the process of endothelial cell activation by TNF-alpha.
Mesh Headings (Keywords): 1-Phosphatidylinositol 3-Kinase, Calcium, Cell Adhesion, Cells, Cultured, Endothelium, Vascular, Enzyme Activation, Humans, Nitric Oxide Synthase Type III, Phosphotransferases (Alcohol Group Acceptor), Proto-Oncogene Proteins c-akt, Receptors, Lysosphingolipid, Signal Transduction, Sphingomyelin Phosphodiesterase, Tumor Necrosis Factor-alpha, Umbilical Veins
Check for Full Text / PubMed Unique Identifier (PMID): 16269668
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.