Document Detail

Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1.
MedLine Citation:
PMID:  18845810     Owner:  NLM     Status:  MEDLINE    
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.
Claude A Piantadosi; Martha Sue Carraway; Abdelwahid Babiker; Hagir B Suliman
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-10-09
Journal Detail:
Title:  Circulation research     Volume:  103     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-25     Completed Date:  2008-12-31     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1232-40     Citation Subset:  IM    
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MeSH Terms
Carbon Monoxide / therapeutic use
DNA, Mitochondrial / genetics
Genes, Reporter
Heme Oxygenase-1 / genetics*,  metabolism*
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
Grant Support
Reg. No./Substance:
0/DNA, Mitochondrial; 0/NF-E2-Related Factor 2; 0/Nrf1 protein, mouse; 0/Nuclear Respiratory Factor 1; 0/RNA, Messenger; 7U1EE4V452/Carbon Monoxide; EC Oxygenase-1; EC protein, mouse; EC Proteins c-akt
Comment In:
Circ Res. 2008 Nov 21;103(11):1191-3   [PMID:  19028915 ]

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