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Cardiovascular Research Advance Access first published online on February 21, 2009
This version [Corrected Proof] published online on March 20, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp072
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia

Ju-Young Kim1,{dagger}, Hyun-Jai Cho1,2,3,{dagger}, Jung-Ju Sir1,2, Baek-Kyung Kim1, Jin Hur1, Seock-Won Youn1, Han-Mo Yang2, Soo-In Jun1, Kyung-Woo Park1,2,3, Seok-Jae Hwang1,2, Yoo-Wook Kwon3, Hae-Young Lee1,2, Hyun-Jae Kang1,2,3, Byung-Hee Oh1,2, Young-Bae Park1,2,3 and Hyo-Soo Kim1,2,3,*

1 National Research Laboratory on Cardiovascular Stem Cell, Seoul National University, College of Medicine, Seoul, Korea
2 Cardiovascular Center, Department of Internal Medicine, Seoul National University Hospital, 28 Yongong-dong, Chongno-gu, Seoul 110-744, Korea
3 Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea

* Corresponding author. Tel: +82 2 2072 2226; fax: +82 2 766 8904. E-mail address: hyosoo{at}snu.ac.kr

Aims: Inflammation, and the subsequent proliferative activity of vascular smooth muscle cells (VSMCs), is one of the major pathophysiological mechanisms associated with neointimal hyperplasia following vascular injury. Although sulfasalazine (SSZ) has been used as an anti-inflammatory and immune-modulatory agent in various inflammatory diseases, its primary targets and therapeutic effects on vascular disease have not yet been determined. We investigated whether SSZ could suppress VSMC growth and prevent neointimal hyperplasia.

Methods and results: SSZ was found to have pro-apoptotic and anti-proliferative activity in cultured VSMCs. Unexpectedly, these effects were not mediated by nuclear factor kappa B (NF-{kappa}B) inhibition, which has been suggested to be the anti-inflammatory mechanism associated with the effects of SSZ. Instead, cell-cycle arrest of the VSMCs was observed, which was mediated by induction of haem oxygenase-1 (HO-1) followed by an increased expression of p21waf1/Cip1. The underlying mechanism for SSZ-induced HO-1 expression was by reactive oxygen species (ROS)-dependent nuclear translocation and activation of nuclear factor erythroid-2-related factor 2 (Nrf2). In a rat carotid artery balloon injury model, administration of SSZ significantly suppressed neointimal growth. In a series of reverse experiments, inhibition of HO-1 by shRNA, ROS by N-acetylcysteine (NAC) or Nrf2 by dominant-negative Nrf2 abrogated the beneficial effects of SSZ.

Conclusion: Our data demonstrate that SSZ inhibits VSMC proliferation in vitro and in vivo through a novel signalling pathway and may be a promising therapeutic option for the treatment of proliferative vascular disease.

KEYWORDS Sulfasalazine; Vascular injury; Reactive oxygen species; haem oxygenase-1; Nuclear factor erythroid-2-related factor 2

Time for primary review: 24 days

{dagger}The first two authors contributed equally to this work.


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