Prednisolone inhibits PDGF-induced nuclear translocation of NF-kappaB in human pulmonary artery smooth muscle cells.
Pulmonary vascular remodeling, a major cause for the elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH), is partially due to increased proliferation of pulmonary arterial smooth muscle cells (PASMC) in the media, resulting in vascular wall thickening. Platelet-derived growth factor (PDGF) is a potent mitogen that may be involved in the progression of PAH. Blockade of PDGF receptors has been demonstrated to have therapeutic potential for patients with severe pulmonary hypertension. Prednisolone is an immunosuppressant shown to have anti-inflammatory and antiproliferative effects on PASMC. This study was designed to investigate whether PDGF and prednisolone affect human PASMC proliferation by regulating the nuclear translocation of NF-kappaB (a transcription factor composed of 2 subunits, p50 and p65). Treatment of human PASMC with PDGF (10 ng/ml) significantly increased nuclear translocation of p50 and p65 subunits. Inhibition of NF-kappaB activation or nuclear translocation of p50/p65 significantly attenuated PDGF-induced PASMC proliferation (determined by [(3)H]thymidine incorporation). In the presence of prednisolone (200 microM), the PDGF-induced nuclear translocation of p50 and p65 subunits was markedly inhibited (P < 0.05 vs. the cells treated with PDGF alone). These results indicate that PDGF-induced nuclear translocation of NF-kappaB may play an important role in stimulating PASMC proliferation (and/or enhancing PASMC survival), whereas prednisolone may exert anti-inflammatory and antiproliferative effects on PASMC by inhibiting NF-kappaB nuclear translocation.
Ogawa
Aiko
A
Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0725, USA.
Firth
Amy L
AL
Yao
Weijuan
W
Rubin
Lewis J
LJ
Yuan
Jason X-J
JX
D000975:Antioxidants / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011239:Prednisolone / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050052:TRPC Cation Channels / Q000235:genetics; D000074287:TRPC6 Cation Channel; D013859:Thiocarbamates / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D000975:Antioxidants; D003470:Culture Media; D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C489571:TRPC4 ion channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D013859:Thiocarbamates; C096351:transient receptor potential cation channel, subfamily C, member 1; C066229:prolinedithiocarbamate; D011392:Proline; D011239:Prednisolone; D013936:Thymidine