Trichostatin A enhances proliferation and migration of vascular smooth muscle cells by downregulating thioredoxin 1.
OBJECTIVE
A reduction in the level of thioredoxin 1 (Trx1) has been proposed as a possible mechanism for the tumor-specific growth arrest caused by inhibition of histone deacetylases (HDACs). In this study, we investigated the effect of trichostatin A (TSA), a potent HDAC inhibitor, on the proliferation and migration of vascular smooth muscle cells (VSMCs), and we examined the role of reduced Trx1 levels in this effect.


RESULTS
TSA treatment time-dependently decreased Trx1 expression in rat VSMCs at both the mRNA and protein levels. It also enhanced platelet-derived growth factor (PDGF)-induced proliferation and migration of the VSMCs. By potentiating Akt phosphorylation, the siRNA-induced downregulation of Trx1 also enhanced VSMC proliferation and migration in response to PDGF or serum treatment. Consistent with these results, TSA administration increased neointimal thickening in a murine model of post-angioplastic restenosis.


CONCLUSIONS
These data demonstrate that TSA enhances vascular proliferative activity by downregulating Trx1, thus activating an Akt-dependent pathway. Our results indicate that, in addition to its apoptotic effects in tumour cells, the downregulation of Trx1 has a proliferative role in primary VSMCs.
Song
Seungjeong
S
Department of Bio and Brain Engineering, KAIST, 335 Gwahangno, Yuseong-gu, Daejeon 305-701, Korea.
Kang
Sang Won
SW
Choi
Chulhee
C
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D019255:NADPH Oxidases / Q000502:physiology; D054464:Peroxiredoxins / Q000235:genetics / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; C012589:trichostatin A; D013879:Thioredoxins; D054464:Peroxiredoxins; D019255:NADPH Oxidases