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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 21, 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 heme oxygenase-1 via ROS-dependent Nrf2 signaling, leading to control of neointimal hyperplasia

Ju-Young Kim, MS*,1, Hyun-Jai Cho, MD, PhD*,1,2,3, Jung-Ju Sir, MD1,2, Baek-Kyung Kim, MS1, Jin Hur, PhD1, Seock-Won Youn, MS1, Han-Mo Yang, MD2, Soo-In Jun, BA1, Kyung-Woo Park, MD, PhD1,2,3, Seok-Jae Hwang, MD1,2, Yoo-Wook Kwon, PhD3, Hae-Young Lee, MD, PhD1,2, Hyun-Jae Kang, MD, PhD1,2,3, Byung-Hee Oh, MD, PhD1,2, Young-Bae Park, MD, PhD1,2,3 and Hyo-Soo Kim, MD, PhD1,2,3

1 National Research Laboratory on Cardiovascular Stem Cell, Seoul National University, College of Medicine,
2 Cardiovascular Center, Department of Internal Medicine, Seoul National University, Hospital,
3 Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea

Correspondence to: Hyo-Soo Kim, MD, PhD, Director of Cardiac Catheterization Laboratory & Coronary Intervention, Director of National Research Laboratory for Cardiovascular Stem Cell, Professor, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 28 Yongong-dong, Chongno-gu, Seoul 110-744, Korea Fax: 82-2- 766-8904 Telephone: 82-2-2072-2226 E-mail: hyosoo{at}snu.ac.kr

Aims: Inflammation, and the subsequent proliferative activity of vascular smooth muscle cells (VSMCs), is one of the major pathophysiologic 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 heme 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 sulfasalazine inhibits VSMC proliferation in vitro and in vivo through a novel signaling pathway and may be a promising therapeutic option for the treatment of proliferative vascular disease.

KEYWORDS sulfasalazine; vascular injury; reactive oxygen species; heme oxygenase-1; nuclear factor erythroid-2 related factor 2

Time for primary review: 24 Days

* The first two authors contributed equally to this work.


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