Download MendeleyBTZO-1, a cardioprotective agent, reveals that macrophage migration inhibitory factor regulates ARE-mediated gene expression
Kimura, H., Sato, Y., Tajima, Y., Suzuki, H., Yukitake, H., Imaeda, T., Kajino, M., Oki, H., Takizawa, M., Tanida, S.(2010) Chem Biol 17: 1282-1294
- PubMed: 21168764
- DOI: https://doi.org/10.1016/j.chembiol.2010.10.011
- Primary Citation of Related Structures:
5B4O - PubMed 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.
Organizational Affiliation:
Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. [email protected]
