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TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo

As a potent and selective allosteric inhibitor of MEK, TAK-733 has been shown to exert anti-cancer effects for a wide range of cancers both in vitro and in vivo. However, its effects on inhibiting growth have never been investigated in the cardiovascular system, where regulation of abnormal vascular...

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Autores principales: Park, Jun-Hee, Kim, Sang Woo, Cha, Min-Ji, Yoon, Nara, Lee, Chang Youn, Lee, Jiyun, Seo, Hyang-Hee, Shin, Sunhye, Choi, Jung-Won, Lee, Seahyoung, Lim, Soyeon, Hwang, Ki-Chul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938062/
https://www.ncbi.nlm.nih.gov/pubmed/29674718
http://dx.doi.org/10.1038/s12276-018-0052-y
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author Park, Jun-Hee
Kim, Sang Woo
Cha, Min-Ji
Yoon, Nara
Lee, Chang Youn
Lee, Jiyun
Seo, Hyang-Hee
Shin, Sunhye
Choi, Jung-Won
Lee, Seahyoung
Lim, Soyeon
Hwang, Ki-Chul
author_facet Park, Jun-Hee
Kim, Sang Woo
Cha, Min-Ji
Yoon, Nara
Lee, Chang Youn
Lee, Jiyun
Seo, Hyang-Hee
Shin, Sunhye
Choi, Jung-Won
Lee, Seahyoung
Lim, Soyeon
Hwang, Ki-Chul
author_sort Park, Jun-Hee
collection PubMed
description As a potent and selective allosteric inhibitor of MEK, TAK-733 has been shown to exert anti-cancer effects for a wide range of cancers both in vitro and in vivo. However, its effects on inhibiting growth have never been investigated in the cardiovascular system, where regulation of abnormal vascular smooth muscle cell growth in neointimal hyperplasia is an important area of focus. Angiotensin II was used to mimic inflammatory neointimal hyperplasia in an in vitro environment, and balloon catheter-induced injury with an infusion of angiotensin II was used to generate an in vivo rat restenosis model under inflammatory conditions. TAK-733 exerted anti-proliferative and anti-migratory effects on human vascular smooth muscle cells. These multiple effects of TAK-733 were evaluated using various assays, such as cell cycle analysis and wound healing. Interestingly, TAK-733 did not induce apoptosis in smooth muscle cells but only reduced the proliferation rate; additionally, it did not affect EC viability. TAK-733 also exhibited anti-inflammatory activity, as observed by attenuated monocyte adhesion to smooth muscle cells via inhibition of ICAM1 and VCAM1 overexpression. The in vivo study demonstrated that neointimal hyperplasia after balloon injury and angiotensin II stimulation was suppressed by TAK-733, and downregulation of the inflammatory signal and enhanced re-endothelialization were observed. TAK-733 may have therapeutic potential for treating neointimal hyperplasia by attenuating smooth muscle cell proliferation, migration, and inflammation. Thus, TAK-733 could be a promising drug candidate for treating patients with restenosis.
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spelling pubmed-59380622018-05-15 TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo Park, Jun-Hee Kim, Sang Woo Cha, Min-Ji Yoon, Nara Lee, Chang Youn Lee, Jiyun Seo, Hyang-Hee Shin, Sunhye Choi, Jung-Won Lee, Seahyoung Lim, Soyeon Hwang, Ki-Chul Exp Mol Med Article As a potent and selective allosteric inhibitor of MEK, TAK-733 has been shown to exert anti-cancer effects for a wide range of cancers both in vitro and in vivo. However, its effects on inhibiting growth have never been investigated in the cardiovascular system, where regulation of abnormal vascular smooth muscle cell growth in neointimal hyperplasia is an important area of focus. Angiotensin II was used to mimic inflammatory neointimal hyperplasia in an in vitro environment, and balloon catheter-induced injury with an infusion of angiotensin II was used to generate an in vivo rat restenosis model under inflammatory conditions. TAK-733 exerted anti-proliferative and anti-migratory effects on human vascular smooth muscle cells. These multiple effects of TAK-733 were evaluated using various assays, such as cell cycle analysis and wound healing. Interestingly, TAK-733 did not induce apoptosis in smooth muscle cells but only reduced the proliferation rate; additionally, it did not affect EC viability. TAK-733 also exhibited anti-inflammatory activity, as observed by attenuated monocyte adhesion to smooth muscle cells via inhibition of ICAM1 and VCAM1 overexpression. The in vivo study demonstrated that neointimal hyperplasia after balloon injury and angiotensin II stimulation was suppressed by TAK-733, and downregulation of the inflammatory signal and enhanced re-endothelialization were observed. TAK-733 may have therapeutic potential for treating neointimal hyperplasia by attenuating smooth muscle cell proliferation, migration, and inflammation. Thus, TAK-733 could be a promising drug candidate for treating patients with restenosis. Nature Publishing Group UK 2018-04-20 /pmc/articles/PMC5938062/ /pubmed/29674718 http://dx.doi.org/10.1038/s12276-018-0052-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, http://creativecommons.org/licenses/by-nc-nd/4.0/.
spellingShingle Article
Park, Jun-Hee
Kim, Sang Woo
Cha, Min-Ji
Yoon, Nara
Lee, Chang Youn
Lee, Jiyun
Seo, Hyang-Hee
Shin, Sunhye
Choi, Jung-Won
Lee, Seahyoung
Lim, Soyeon
Hwang, Ki-Chul
TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo
title TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo
title_full TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo
title_fullStr TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo
title_full_unstemmed TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo
title_short TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo
title_sort tak-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938062/
https://www.ncbi.nlm.nih.gov/pubmed/29674718
http://dx.doi.org/10.1038/s12276-018-0052-y
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