Sphingosine-1-phosphate induces COX-2 expression via PI3K/Akt and p42/p44 MAPK pathways in rat vascular smooth muscle cells

Autor: Chang-Hui Liao, Chou-Bing Wu, Ying-Tung Lau, Hsi-Lung Hsieh, Chuen-Mao Yang, Chi-Chin Sun
Rok vydání: 2006
Předmět:
MAPK/ERK pathway
Vascular smooth muscle
Transcription
Genetic
Physiology
Clinical Biochemistry
Myocytes
Smooth Muscle
Biology
environment and public health
Gene Expression Regulation
Enzymologic
Muscle
Smooth
Vascular
Wortmannin
Rats
Sprague-Dawley
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
Sphingosine
Nitriles
Butadienes
Animals
LY294002
Extracellular Signal-Regulated MAP Kinases
Promoter Regions
Genetic
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Cells
Cultured
Phosphoinositide-3 Kinase Inhibitors
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Kinase
NF-kappa B
Cell Biology
Cell biology
Rats
enzymes and coenzymes (carbohydrates)
Protein Transport
chemistry
Cyclooxygenase 2
lipids (amino acids
peptides
and proteins)
biological phenomena
cell phenomena
and immunity
Signal transduction
Lysophospholipids
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: Journal of cellular physiology. 207(3)
ISSN: 0021-9541
Popis: Sphingosine 1-phosphate (S1P) has been shown to regulate smooth muscle cell proliferation, migration, and vascular maturation. S1P increases the expression of several proteins including COX-2 in vascular smooth muscle cells (VSMCs) and contributes to arteriosclerosis. However, the mechanisms regulating COX-2 expression by S1P in VSMCs remain unclear. Western blotting and RT-PCR analyses showed that S1P induced the expression of COX-2 mRNA and protein in a time- and concentration-dependent manner, which was attenuated by inhibitors of MEK1/2 (U0126) and PI3K (wortmannin), and transfection with dominant negative mutants of p42/p44 mitogen-activated protein kinases (ERK2) or Akt. These results suggested that both p42/p44 MAPK and PI3K/Akt pathways participated in COX-2 expression induced by S1P in VSMCs. In accordance with these findings, S1P stimulated phosphorylation of p42/p44 MAPK and Akt, which was attenuated by U0126, LY294002, or wortmannin, respectively. Furthermore, this up-regulation of COX-2 mRNA and protein was blocked by a selective NF-kappaB inhibitor helenalin. Consistently, S1P-stimulated translocation of NF-kappaB into the nucleus was revealed by immnofluorescence staining. Moreover, S1P-stimulated activation of NF-kappaB promoter activity was blocked by phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and helenalin, but not by U0126, suggesting that involvement of PI3K/Akt in the activation of NF-kappaB. COX-2 promoter assay showed that S1P induced COX-2 promoter activity mediated through p42/p44 MAPK, PI3K/Akt, and NF-kappaB. These results suggested that in VSMCs, activation of p42/p44 MAPK, Akt and NF-kappaB pathways was essential for S1P-induced COX-2 gene expression. Understanding the mechanisms involved in S1P-induced COX-2 expression on VSMCs may provide potential therapeutic targets in the treatment of arteriosclerosis.
Databáze: OpenAIRE
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