Effects of a stable prostacyclin analogue beraprost sodium on VEGF and PAI-1 gene expression in vascular smooth muscle cells.
BACKGROUND
Beraprost sodium, an orally active prostacyclin analogue, has proved to be beneficial for the patients with primary pulmonary hypertension and obstructive peripheral arterial disease.


METHODS
In this study, we examined the effects of BPS on the expression of the VEGF and PAI-1 genes in vascular smooth muscle cells.


RESULTS
The mRNA levels for VEGF were increased by BPS in C2/2 cells and cultured rat aortic smooth muscle cells. In contrast, PAI-1 mRNA levels were significantly decreased by BPS. Luciferase assays and mRNA decay assays showed that BPS increases VEGF promoter activity and has no effects on its mRNA stability. Likewise, BPS decreases PAI-1 promoter activity without affecting its mRNA stability. Experiments using various pharmacological inhibitors for protein kinases showed that activation of cAMP-dependent protein kinase (PKA) was involved in BPS-mediated regulation of VEGF and PAI-1 mRNA expression. Overexpression of CREB (cAMP-responsive element binding protein) induces VEGF promoter and reduces PAI-1 promoter activities. CREMepsilon, a dominant negative form of CREB, inhibits BPS-mediated changes in VEGF and PAI-1 promoter activities. While BPS augmented hypoxia-induced VEGF mRNA expression, it blunted hypoxia-induced PAI-1 mRNA expression.


CONCLUSIONS
These results suggest that BPS increases VEGF and decreases PAI-1 gene expression through PKA/CREB-dependent mechanisms in vascular smooth muscle cells. Because these effects are observed more prominently under the hypoxic condition compared to normoxic condition, BPS may have a potential to relieve hypoxia by inducing neovasculization and by reducing thrombosis.
Atsuta
Hiroyuki
H
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Uchiyama
Tsuyoshi
T
Kanai
Hiroyoshi
H
Iso
Tatsuya
T
Tanaka
Toru
T
Suga
Tatsuo
T
Maeno
Toshitaka
T
Arai
Masashi
M
Nagai
Ryozo
R
Kurabayashi
Masahiko
M
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000528:radiation effects; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology*
D017362:Cyclic AMP Response Element-Binding Protein; D017395:Plasminogen Activator Inhibitor 1; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; C048081:beraprost; D011464:Epoprostenol; D017868:Cyclic AMP-Dependent Protein Kinases