BTZO-1, a cardioprotective agent, reveals that macrophage migration inhibitory factor regulates ARE-mediated gene expression

  • Chem Biol. 2010 Dec 22;17(12):1282-94. doi: 10.1016/j.chembiol.2010.10.011.
Haruhide Kimura  1 ,  Yoshimi Sato ,  Yasukazu Tajima ,  Hirobumi Suzuki ,  Hiroshi Yukitake ,  Toshihiro Imaeda ,  Masahiro Kajino ,  Hideyuki Oki ,  Masayuki Takizawa ,  Seiichi Tanida
Affiliations
  • 1. Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. [email protected]
PMID: 21168764 DOI: 10.1016/j.chembiol.2010.10.011
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.

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