Back to Search
Start Over
Autocrine expression of osteopontin contributes to PDGF-mediated arterial smooth muscle cell migration.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2007 Sep 01; Vol. 75 (4), pp. 738-47. Date of Electronic Publication: 2007 May 24. - Publication Year :
- 2007
-
Abstract
- Objective: Migration of smooth muscle cells (SMCs) from the media to the intima of arteries is involved in intimal thickening. The platelet-derived growth factor (PDGF) BB is recognized as a major migratory factor for arterial SMCs both in vitro and during neointima formation. Since PDGF acts in synergy with the matrix protein osteopontin (OPN) and also induces its expression, the present study was conceived to explore the role of the OPN produced in an autocrine fashion by PDGF-stimulated SMCs in the migration process and to define regulatory mechanisms of OPN expression.<br />Methods and Results: PDGF stimulation of quiescent rat aortic SMCs induced their migration (transfilter assays) and the increase of OPN expression (mRNA and protein assays). Blockade of either OPN expression by a specific short interference RNA (siRNA) or of its function by a blocking antibody decreased the PDGF-stimulated migration by about 70%, demonstrating that autocrine production and excretion of OPN are integral to the PDGF-induced SMC migration. In parallel, SMC stimulation by PDGF also activated the transcription factor CREB essentially through mitogen-activated protein kinase (MAPK) 1/2 and protein kinase A (PKA) pathways. Inhibition of either CREB expression (via siRNA) or function (via dominant-negative CREB) decreased both PDGF-induced SMC migration and OPN expression. SMC transfection with OPN promoter reporter constructs demonstrated that PDGF-induced OPN transcription is mediated by CREB binding to two functional sites of the OPN promoter: a CRE site located at -1403 and an AP-1 site located at -76.<br />Conclusion: The present study demonstrates that the autocrine expression of OPN plays a major role in PDGF-induced SMC migration. It further shows that the transcription factor CREB, activated in PDGF-stimulated SMCs, plays a key role in PDGF-induced SMC migration, probably by regulating OPN expression.
- Subjects :
- Animals
Atherosclerosis metabolism
Atherosclerosis pathology
Becaplermin
Calcinosis metabolism
Cell Movement physiology
Cells, Cultured
Cyclic AMP Response Element-Binding Protein analysis
Cyclic AMP Response Element-Binding Protein genetics
Cyclic AMP Response Element-Binding Protein metabolism
Cyclic AMP-Dependent Protein Kinases metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
Osteopontin analysis
Osteopontin genetics
Platelet-Derived Growth Factor pharmacology
Proto-Oncogene Proteins c-sis
RNA Interference
RNA, Messenger analysis
RNA, Small Interfering pharmacology
Rats
Rats, Wistar
Stimulation, Chemical
Transcription, Genetic drug effects
Transfection methods
Autocrine Communication physiology
Myocytes, Smooth Muscle metabolism
Myocytes, Smooth Muscle pathology
Osteopontin physiology
Platelet-Derived Growth Factor metabolism
Tunica Intima pathology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-6363
- Volume :
- 75
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 17574222
- Full Text :
- https://doi.org/10.1016/j.cardiores.2007.05.019