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Role of Bach1 and Nrf2 in up-regulation of the heme oxygenase-1 gene by cobalt protoporphyrin

Ying Shan^*,,1, Richard W. Lambrecht^,, Susan E. Donohue^*, and Herbert L. Bonkovsky^*,,

^* Department of Medicine,

the Liver-Biliary-Pancreatic Center, Departments of

Pharmacology and

Molecular, Microbial and Structural Biology of the University of Connecticut Health Center, Farmington, Connecticut, USA

¹Correspondence: 263 Farmington Ave. MC-1119, Farmington, CT 06030, USA. E-mail: shan{at}uchc.edu

ABSTRACT

Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin with the release of iron and carbon monoxide. HO-1 is highly inducible by a large number of physical and chemical factors. CoPP is known to be a potent and effective inducer of HO-1 activity in many tissues. Here we report that CoPP up-regulates HO-1 via Bach1 and Nrf2 in human liver cells. CoPP did not influence hepatic Bach1 or Nrf2 mRNA levels, but markedly reduced Bach1 protein levels by increasing degradation of Bach1 protein (t_1/2 from 19 h to 2.8 h), and increased Nrf2 by decreasing degradation of Nrf2 protein (t_1/2 from 2.5 h to 9 h). Silencing Bach1 by Bach1-siRNA significantly increased levels of HO-1 mRNA and protein, and addition of CoPP up-regulated HO-1 mRNA and protein further. However, silencing Nrf2 mRNA by Nrf2-siRNA did not significantly change baseline HO-1 mRNA or protein levels, but significantly decreased 5–10 µM CoPP-mediated up-regulation of HO-1 mRNA levels compared with CoPP alone. Transfection with equal amounts of non-Bach1 or non-Nrf2 related control siRNA did not reduce Bach1 or Nrf2 mRNA or protein, confirming the specificity of Bach1- and Nrf2-siRNA in Huh-7 cells. We conclude that the pathway of CoPP-mediated induction of HO-1 involves the repression of Bach1 and up-regulation of the Nrf2 protein by post-transcriptional site(s) of action. Because CoPP, unlike heme, is neither a prooxidant nor a substrate for HO-1, it might be considered as a potential therapeutic agent in situations where up-regulation of HO-1 is desired.—Shan, Y., Lambrecht, R. W., Donohue, S. E., Bonkovsky, H. L. Role of Bach1 and Nrf2 in up-regulation of the heme oxygenase-1 gene by cobalt protoporphyrin.

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