HO-1 (haem oxygenase 1) is an essential antioxidant enzyme in the cell that exerts its effects through removal of pro-oxidant haem groups and the formation of antioxidant molecules and carbon monoxide. The electrophilic cyclopentenone 15d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2) induces the expression of HO-1 protein through the covalent modification of protein thiols. It has been shown that specific thiol residues of the redox-sensor Keap1 (Kelch-like ECH-associated protein 1) are modified by 15d-PGJ2, leading to activation of the transcription factor Nrf-2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) and up-regulation of genes under control of the electrophile-response element, including HO-1. However, 15d-PGJ2 has also been shown to modify other proteins which comprise the electrophile-responsive proteome. Since 15d-PGJ2 has been shown to localize to the mitochondria in endothelial cells, we hypothesized that mitochondrial protein modification may also be important in Keap1/Nrf-2 signal transduction, leading to HO-1 up-regulation. In order to determine the role of mitochondrial protein thiol modification in HO-1 induction, we used the mitochondrial-targeted thiol-reactive compound IBTP [(4-iodobutyl)triphenylphosphonium]. IBTP had no effect on basal HO-1 levels, but effectively blocked HO-1 induction by a variety of reagents including haemin, iodoacetamide and 15d-PGJ2. Mechanistically, IBTP did not prevent the covalent modification of Keap1 by 15d-PGJ2. However, IBTP prevented the 15d-PGJ2-dependent increases in HO-1 mRNA and protein. Furthermore, IBTP prevented the nuclear accumulation of Nrf-2, suggesting cross-talk between mitochondria and antioxidant-response signal transduction. This effect was independent of reactive oxygen species formation or mitochondrial membrane potential. In addition, IBTP significantly enhanced the toxicity of high concentrations of 15d-PGJ2, suggesting that loss of mitochondrial control of HO-1 leads to increased susceptibility to electrophilic stress in endothelial cells. The implications for these studies in understanding the balance between cytoprotection and cytotoxicity in the context of diseases such as atherosclerosis is discussed.
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Research Article|
March 27 2009
The permissive role of mitochondria in the induction of haem oxygenase-1 in endothelial cells
Karina C. Ricart;
Karina C. Ricart
*Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
†Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
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Subhashini Bolisetty;
Subhashini Bolisetty
†Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
‡Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
§Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
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Michelle S. Johnson;
Michelle S. Johnson
*Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
†Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
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Jessica Perez;
Jessica Perez
*Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
†Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
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Anupam Agarwal;
Anupam Agarwal
†Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
‡Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
§Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
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Michael P. Murphy;
Michael P. Murphy
∥MRC-Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, U.K.
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Aimee Landar
Aimee Landar
1
*Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
†Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
§Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294-2180, U.S.A.
1To whom correspondence should be addressed (email landar@uab.edu).
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Publisher: Portland Press Ltd
Received:
July 01 2008
Revision Received:
January 13 2009
Accepted:
January 23 2009
Accepted Manuscript online:
January 23 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 419 (2): 427–436.
Article history
Received:
July 01 2008
Revision Received:
January 13 2009
Accepted:
January 23 2009
Accepted Manuscript online:
January 23 2009
Citation
Karina C. Ricart, Subhashini Bolisetty, Michelle S. Johnson, Jessica Perez, Anupam Agarwal, Michael P. Murphy, Aimee Landar; The permissive role of mitochondria in the induction of haem oxygenase-1 in endothelial cells. Biochem J 15 April 2009; 419 (2): 427–436. doi: https://doi.org/10.1042/BJ20081350
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