Back to Search
Start Over
The sphingosine kinase inhibitor N,N-dimethylsphingosine inhibits neointimal hyperplasia.
- Source :
- British Journal of Pharmacology; Feb2010, Vol. 159 Issue 3, p543-553, 11p
- Publication Year :
- 2010
-
Abstract
- <bold>Background and Purpose: </bold>Sphingosine-1-phosphate and its receptors may be involved in vascular smooth muscle cell (VSMC) proliferation following vascular injury. Here, we evaluate the effect of d-erythro-N,N-dimethylsphingosine (DMS), a sphingosine kinase (SK) inhibitor, on VSMC proliferation, apoptosis and neointimal formation.<bold>Experimental Approach: </bold>Growth responses in vitro to fetal calf serum (FCS) were measured by [(3)H]-thymidine incorporation and extracellular signal-regulated kinase-1/2 (ERK-1/2) activation in quiescent primary cultures of porcine VSMC in the presence and absence of various concentrations of the SK inhibitor DMS. In vivo treatment with DMS was delivered with a local endoluminal catheter, following balloon injury of coronary arteries. The artery intimal formation was investigated by angiography, myography and histomorphometry.<bold>Key Results: </bold>In vitro experiments indicated that DMS induced a dose-dependent reduction in [(3)H]-thymidine incorporation and ERK-1/2 activation via a protein kinase C (PKC) independent mechanism with an IC(50) value of 12 +/- 6 and 15 +/- 10 microM respectively. DMS also reduced Akt signalling. Four weeks following in vivo delivery of DMS, complete functional endothelial regeneration was observed in all treatment groups, with significant reduction of intimal formation (vehicle 23.7 +/- 4.6% vs. DMS infusion 8.92 +/- 2.9%, P < 0.05).<bold>Conclusions and Implications: </bold>Taken together, these results demonstrate that local administration of the SK inhibitor, DMS, reduced neointimal formation, and this effect could involve inhibition of ERK-1/2 and Akt signalling, and modulation of smooth muscle growth. [ABSTRACT FROM AUTHOR]
- Subjects :
- SPHINGOSINE
HYPERPLASIA
VASCULAR smooth muscle
CELL proliferation
VASCULAR diseases
APOPTOSIS
CORONARY restenosis
PROTEIN kinase C
CELL metabolism
ANIMAL experimentation
BLOOD vessels
CATHETERIZATION
CELL physiology
CELLULAR signal transduction
COMPARATIVE studies
GLYCOLS
RESEARCH methodology
MEDICAL cooperation
PHOSPHOLIPIDS
RESEARCH
RESEARCH funding
SMOOTH muscle
SWINE
TRANSFERASES
EVALUATION research
PROTEIN kinase inhibitors
PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 159
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 65012774
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2009.00533.x