Abstract |
Heme oxygenase (HO)-1 is a protective antioxidant enzyme that prevents cardiomyocyte apoptosis, for instance, during progressive cardiomyopathy. Here we identify a fundamental aspect of the HO-1 protection mechanism by demonstrating that HO-1 activity in mouse heart stimulates the bigenomic mitochondrial biogenesis program via induction of NF-E2-related factor (Nrf)2 gene expression and nuclear translocation. Nrf2 upregulates the mRNA, protein, and activity for HO-1 as well as mRNA and protein for nuclear respiratory factor (NRF)-1. Mechanistically, in cardiomyocytes, endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H(2)O(2) production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3beta, which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter. The ensuing accumulation of nuclear NRF-1 protein leads to gene activation for mitochondrial biogenesis, which opposes apoptosis and necrosis caused by the cardio-toxic anthracycline chemotherapeutic agent, doxorubicin. In cardiac cells, Akt silencing exacerbates doxorubicin-induced apoptosis, and in vivo CO rescues wild-type but not Akt1(-/-) mice from doxorubicin cardiomyopathy. These findings consign HO-1/CO signaling through Nrf2 and Akt to the myocardial transcriptional program for mitochondrial biogenesis, provide a rationale for targeted mitochondrial CO therapy, and connect cardiac mitochondrial volume expansion with the inducible network of xenobiotic and antioxidant cellular defenses.
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Authors | Claude A Piantadosi, Martha Sue Carraway, Abdelwahid Babiker, Hagir B Suliman |
Journal | Circulation research
(Circ Res)
Vol. 103
Issue 11
Pg. 1232-40
(Nov 21 2008)
ISSN: 1524-4571 [Electronic] United States |
PMID | 18845810
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- DNA, Mitochondrial
- NF-E2-Related Factor 2
- Nrf1 protein, mouse
- Nuclear Respiratory Factor 1
- RNA, Messenger
- Carbon Monoxide
- Heme Oxygenase-1
- Akt1 protein, mouse
- Proto-Oncogene Proteins c-akt
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Topics |
- Animals
- Carbon Monoxide
(therapeutic use)
- DNA, Mitochondrial
(genetics)
- Genes, Reporter
- Heme Oxygenase-1
(genetics, metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mitochondria, Heart
(physiology)
- Myocytes, Cardiac
(physiology)
- NF-E2-Related Factor 2
(genetics, physiology)
- Nuclear Respiratory Factor 1
(genetics)
- Polymerase Chain Reaction
- Promoter Regions, Genetic
- Proto-Oncogene Proteins c-akt
(deficiency, genetics)
- RNA, Messenger
(genetics)
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