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

Ju Young Kim, Hyun Jai Cho, Jung Ju Sir, Baek Kyung Kim, Jin Hur, Seock Won Youn, Han Mo Yang, Soo In Jun, Kyung Woo Park, Seok Jae Hwang, Yoo Wook Kwon, Hae Young Lee, Hyun Jae Kang, Byung Hee Oh, Young Bae Park, Hyo Soo Kim

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

AimsInflammation, 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 resultsSSZ 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-κB) 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.ConclusionOur 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.

Original languageEnglish (US)
Pages (from-to)550-560
Number of pages11
JournalCardiovascular Research
Volume82
Issue number3
DOIs
StatePublished - Jun 1 2009

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Heme Oxygenase (Decyclizing)
Sulfasalazine
Hyperplasia
Reactive Oxygen Species
Vascular Smooth Muscle
Smooth Muscle Myocytes
Vascular Diseases
Anti-Inflammatory Agents
Carotid Artery Injuries
NF-kappa B
Vascular System Injuries
Acetylcysteine
Therapeutic Uses
Growth
Cell Cycle Checkpoints
Small Interfering RNA
Cell Proliferation

Keywords

  • Haem oxygenase-1
  • Nuclear factor erythroid-2-related factor 2
  • Reactive oxygen species
  • Sulfasalazine
  • Vascular injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia. / Kim, Ju Young; Cho, Hyun Jai; Sir, Jung Ju; Kim, Baek Kyung; Hur, Jin; Youn, Seock Won; Yang, Han Mo; Jun, Soo In; Park, Kyung Woo; Hwang, Seok Jae; Kwon, Yoo Wook; Lee, Hae Young; Kang, Hyun Jae; Oh, Byung Hee; Park, Young Bae; Kim, Hyo Soo.

In: Cardiovascular Research, Vol. 82, No. 3, 01.06.2009, p. 550-560.

Research output: Contribution to journalArticle

Kim, JY, Cho, HJ, Sir, JJ, Kim, BK, Hur, J, Youn, SW, Yang, HM, Jun, SI, Park, KW, Hwang, SJ, Kwon, YW, Lee, HY, Kang, HJ, Oh, BH, Park, YB & Kim, HS 2009, 'Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia', Cardiovascular Research, vol. 82, no. 3, pp. 550-560. https://doi.org/10.1093/cvr/cvp072
Kim, Ju Young ; Cho, Hyun Jai ; Sir, Jung Ju ; Kim, Baek Kyung ; Hur, Jin ; Youn, Seock Won ; Yang, Han Mo ; Jun, Soo In ; Park, Kyung Woo ; Hwang, Seok Jae ; Kwon, Yoo Wook ; Lee, Hae Young ; Kang, Hyun Jae ; Oh, Byung Hee ; Park, Young Bae ; Kim, Hyo Soo. / Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia. In: Cardiovascular Research. 2009 ; Vol. 82, No. 3. pp. 550-560.
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abstract = "AimsInflammation, 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 resultsSSZ 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-κB) 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.ConclusionOur 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.",
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AU - Cho, Hyun Jai

AU - Sir, Jung Ju

AU - Kim, Baek Kyung

AU - Hur, Jin

AU - Youn, Seock Won

AU - Yang, Han Mo

AU - Jun, Soo In

AU - Park, Kyung Woo

AU - Hwang, Seok Jae

AU - Kwon, Yoo Wook

AU - Lee, Hae Young

AU - Kang, Hyun Jae

AU - Oh, Byung Hee

AU - Park, Young Bae

AU - Kim, Hyo Soo

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N2 - AimsInflammation, 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 resultsSSZ 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-κB) 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.ConclusionOur 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.

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KW - Nuclear factor erythroid-2-related factor 2

KW - Reactive oxygen species

KW - Sulfasalazine

KW - Vascular injury

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