Chemistry & Biology
Volume 17, Issue 12, 22 December 2010, Pages 1282-1294
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Article
BTZO-1, a Cardioprotective Agent, Reveals that Macrophage Migration Inhibitory Factor Regulates ARE-Mediated Gene Expression

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Summary

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 Kd 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.

Highlights

► ARE activation is involved in cellular protection against oxidative stress ► MIF is a ubiquitous protein with conserved nucleophilic Pro1 in a hydrophobic pocket ► BTZO-1 selectively binds to MIF, and its binding required the intact N-terminal Pro1 ► Binding of BTZO-1 to MIF leads to the ARE activation in cardiomyocytes.

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