3,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury.
3,3'Diindolylmethane (DIM), a natural phytochemical, has shown inhibitory effects on the growth and migration of a variety of cancer cells; however, whether DIM has similar effects on vascular smooth muscle cells (VSMCs) remains unknown. The purpose of this study was to assess the effects of DI...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2012-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC3323601?pdf=render |
id |
doaj-345df760192e4f2eb9262db77db86b0a |
---|---|
record_format |
Article |
spelling |
doaj-345df760192e4f2eb9262db77db86b0a2020-11-24T20:50:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0174e3495710.1371/journal.pone.00349573,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury.Hongjing GuanLihua ZhuMingyue FuDa YangSong TianYuanyuan GuoChangping CuiLang WangHong Jiang3,3'Diindolylmethane (DIM), a natural phytochemical, has shown inhibitory effects on the growth and migration of a variety of cancer cells; however, whether DIM has similar effects on vascular smooth muscle cells (VSMCs) remains unknown. The purpose of this study was to assess the effects of DIM on the proliferation and migration of cultured VSMCs and neointima formation in a carotid injury model, as well as the related cell signaling mechanisms.DIM dose-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of VSMCs without cell cytotoxicity. This inhibition was caused by a G0/G1 phase cell cycle arrest demonstrated by fluorescence-activated cell-sorting analysis. We also showed that DIM-induced growth inhibition was associated with the inhibition of the expression of cyclin D1 and cyclin-dependent kinase (CDK) 4/6 as well as an increase in p27(Kip1) levels in PDGF-stimulated VSMCs. Moreover, DIM was also found to modulate migration of VSMCs and smooth muscle-specific contractile marker expression. Mechanistically, DIM negatively modulated PDGF-BB-induced phosphorylation of PDGF-recptorβ (PDGF-Rβ) and the activities of downstream signaling molecules including Akt/glycogen synthase kinase(GSK)3β, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3). Our in vivo studies using a mouse carotid arterial injury model revealed that treatment with 150 mg/kg DIM resulted in significant reduction of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells, without affecting apoptosis of vascular cells and reendothelialization. Infiltration of inflammatory cells was also inhibited by DIM administration.These results demonstrate that DIM can suppress the phenotypic modulation of VSMCs and neointima hyperplasia after vascular injury. These beneficial effects on VSMCs were at least partly mediated by the inhibition of PDGF-Rβ and the activities of downstream signaling pathways. The results suggest that DIM has the potential to be a candidate for the prevention of restenosis.http://europepmc.org/articles/PMC3323601?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hongjing Guan Lihua Zhu Mingyue Fu Da Yang Song Tian Yuanyuan Guo Changping Cui Lang Wang Hong Jiang |
spellingShingle |
Hongjing Guan Lihua Zhu Mingyue Fu Da Yang Song Tian Yuanyuan Guo Changping Cui Lang Wang Hong Jiang 3,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury. PLoS ONE |
author_facet |
Hongjing Guan Lihua Zhu Mingyue Fu Da Yang Song Tian Yuanyuan Guo Changping Cui Lang Wang Hong Jiang |
author_sort |
Hongjing Guan |
title |
3,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury. |
title_short |
3,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury. |
title_full |
3,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury. |
title_fullStr |
3,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury. |
title_full_unstemmed |
3,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury. |
title_sort |
3,3'diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
3,3'Diindolylmethane (DIM), a natural phytochemical, has shown inhibitory effects on the growth and migration of a variety of cancer cells; however, whether DIM has similar effects on vascular smooth muscle cells (VSMCs) remains unknown. The purpose of this study was to assess the effects of DIM on the proliferation and migration of cultured VSMCs and neointima formation in a carotid injury model, as well as the related cell signaling mechanisms.DIM dose-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of VSMCs without cell cytotoxicity. This inhibition was caused by a G0/G1 phase cell cycle arrest demonstrated by fluorescence-activated cell-sorting analysis. We also showed that DIM-induced growth inhibition was associated with the inhibition of the expression of cyclin D1 and cyclin-dependent kinase (CDK) 4/6 as well as an increase in p27(Kip1) levels in PDGF-stimulated VSMCs. Moreover, DIM was also found to modulate migration of VSMCs and smooth muscle-specific contractile marker expression. Mechanistically, DIM negatively modulated PDGF-BB-induced phosphorylation of PDGF-recptorβ (PDGF-Rβ) and the activities of downstream signaling molecules including Akt/glycogen synthase kinase(GSK)3β, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3). Our in vivo studies using a mouse carotid arterial injury model revealed that treatment with 150 mg/kg DIM resulted in significant reduction of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells, without affecting apoptosis of vascular cells and reendothelialization. Infiltration of inflammatory cells was also inhibited by DIM administration.These results demonstrate that DIM can suppress the phenotypic modulation of VSMCs and neointima hyperplasia after vascular injury. These beneficial effects on VSMCs were at least partly mediated by the inhibition of PDGF-Rβ and the activities of downstream signaling pathways. The results suggest that DIM has the potential to be a candidate for the prevention of restenosis. |
url |
http://europepmc.org/articles/PMC3323601?pdf=render |
work_keys_str_mv |
AT hongjingguan 33diindolylmethanesuppressesvascularsmoothmusclecellphenotypicmodulationandinhibitsneointimaformationaftercarotidinjury AT lihuazhu 33diindolylmethanesuppressesvascularsmoothmusclecellphenotypicmodulationandinhibitsneointimaformationaftercarotidinjury AT mingyuefu 33diindolylmethanesuppressesvascularsmoothmusclecellphenotypicmodulationandinhibitsneointimaformationaftercarotidinjury AT dayang 33diindolylmethanesuppressesvascularsmoothmusclecellphenotypicmodulationandinhibitsneointimaformationaftercarotidinjury AT songtian 33diindolylmethanesuppressesvascularsmoothmusclecellphenotypicmodulationandinhibitsneointimaformationaftercarotidinjury AT yuanyuanguo 33diindolylmethanesuppressesvascularsmoothmusclecellphenotypicmodulationandinhibitsneointimaformationaftercarotidinjury AT changpingcui 33diindolylmethanesuppressesvascularsmoothmusclecellphenotypicmodulationandinhibitsneointimaformationaftercarotidinjury AT langwang 33diindolylmethanesuppressesvascularsmoothmusclecellphenotypicmodulationandinhibitsneointimaformationaftercarotidinjury AT hongjiang 33diindolylmethanesuppressesvascularsmoothmusclecellphenotypicmodulationandinhibitsneointimaformationaftercarotidinjury |
_version_ |
1716803878295437312 |