title: BTZO-1, a cardioprotective agent, reveals that macrophage migration inhibitory factor regulates ARE-mediated gene expression.
abstract: In a screening program to discover therapeutic drugs for heart diseases, we identified BTZO-1, a 1,3-benzothiazin-4-one derivative, which activated antioxidant response element (ARE)-mediated gene expression and suppressed oxidative stress-induced cardiomyocyte apoptosis in vitro. An active BTZO-1 derivative for ARE-activation protected heart tissue during ischemia/reperfusion injury in rats. Macrophage migration inhibitory factor (MIF), which is known to protect cells from oxidative insult, was identified as a specific BTZO-1-binding protein. BTZO-1 binds to MIF with a K(d) of 68.6 nM, and its binding required the intact N-terminal Pro1. MIF, in the presence of BTZO-1, activated the glutathione S-transferase Ya subunit (GST Ya) gene ARE, whereas reduction of cellular MIF protein levels by siRNA suppressed BTZO-1-induced GST Ya expression. These results suggest that BTZO-1 activates the GST Ya gene ARE by interacting with MIF.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. kimura_haruhide@takeda.co.jp
authors.forename: Haruhide
authors.initials: H
authors.lastname: Kimura
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Sato
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Tajima
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yukitake
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Imaeda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajino
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takizawa
authors.forename: Seiichi
authors.initials: S
authors.lastname: Tanida
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000494:pharmacology; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D032383:Myocytes, Cardiac / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D020218:Response Elements; D013843:Thiazines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C557081:2-pyridin-2-yl-4H-1,3-benzothiazin-4-one; D000975:Antioxidants; D002316:Cardiotonic Agents; D008263:Macrophage Migration-Inhibitory Factors; D011725:Pyridines; D034741:RNA, Small Interfering; D013843:Thiazines; D009569:Nitric Oxide; D005982:Glutathione Transferase