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

Exp Mol Med. 2018 Apr 20;50(4):1-12. doi: 10.1038/s12276-018-0052-y.

Jun-Hee Park ^# ¹, Sang Woo Kim ^# ² ³, Min-Ji Cha ^# ², Nara Yoon ⁴, Chang Youn Lee ¹, Jiyun Lee ⁵, Hyang-Hee Seo ⁵, Sunhye Shin ¹, Jung-Won Choi ² ⁶, Seahyoung Lee ² ³, Soyeon Lim ⁷ ⁸, Ki-Chul Hwang ⁹ ¹⁰

Affiliations

1 Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul, 03722, Korea.
2 Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, 25601, Korea.
3 Catholic Kwandong University International St. Mary's Hospital, Incheon, 22711, Korea.
4 Department of Pathology, The Catholic University of Korea, Incheon St. Mary's Hospital, Incheon, Korea.
5 Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, 03722, Korea.
6 Department of Environmental Engineering, Catholic Kwandong University, Gangneung-si, Gangwon-do, 210-701, Korea.
7 Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, 25601, Korea. slim724@cku.ac.kr.
8 Catholic Kwandong University International St. Mary's Hospital, Incheon, 22711, Korea. slim724@cku.ac.kr.
9 Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, 25601, Korea. kchwang@cku.ac.kr.
10 Catholic Kwandong University International St. Mary's Hospital, Incheon, 22711, Korea. kchwang@cku.ac.kr.
# Contributed equally.

PMID: 29674718 DOI: 10.1038/s12276-018-0052-y

Abstract

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-13449

TAK-733

98.31%, MEK Inhibitor

MEK

Cancer

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