DHEA attenuates PDGF-induced phenotypic proliferation of vascular smooth muscle A7r5 cells through redox regulation.
It is known that dehydroepiandrosterone (DHEA) inhibits a phenotypic switch in vascular smooth muscle cells (VSMC) induced by platelet-derived growth factor (PDGF)-BB. However, the mechanism behind the effect of DHEA on VSMC is not clear. Previously we reported that low molecular weight-protein tyrosine phosphatase (LMW-PTP) dephosphorylates PDGF receptor (PDGFR)-beta via a redox-dependent mechanism involving glutathione (GSH)/glutaredoxin (GRX)1. Here we demonstrate that the redox regulation of PDGFR-beta is involved in the effect of DHEA on VSMC. DHEA suppressed the PDGF-BB-dependent phosphorylation of PDGFR-beta. As expected, DHEA increased the levels of GSH and GRX1, and the GSH/GRX1 system maintained the redox state of LMW-PTP. Down-regulation of the expression of LMW-PTP using siRNA restored the suppression of PDGFR-beta-phosphorylation by DHEA. A promoter analysis of GRX1 and gamma-glutamylcysteine synthetase (gamma-GCS), a rate-limiting enzyme of GSH synthesis, showed that DHEA up-regulated the transcriptional activity at the peroxisome proliferator-activated receptor (PPAR) response element, suggesting PPARalpha plays a role in the induction of GRX1 and gamma-GCS expression by DHEA. In conclusion, the redox regulation of PDGFR-beta is involved in the suppressive effect of DHEA on VSMC proliferation through the up-regulation of GSH/GRX system.
Urata
Yoshishige
Y
Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Medical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Goto
Shinji
S
Kawakatsu
Miho
M
Yodoi
Junji
J
Eto
Masato
M
Akishita
Masahiro
M
Kondo
Takahito
T
D000818:Animals; D000077214:Becaplermin; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D014162:Transfection
C516007:Glrx protein, rat; D054477:Glutaredoxins; D007527:Isoenzymes; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D000077214:Becaplermin; D003687:Dehydroepiandrosterone; D020797:Receptor, Platelet-Derived Growth Factor beta; C091645:Acp1 protein, rat; D017027:Protein Tyrosine Phosphatases; D005978:Glutathione