| 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 |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
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: 2011-07-14 |
Medline Journal Info:
|
Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
|
Languages: eng Pagination: 1232-40 Citation Subset: IM |
Affiliation:
|
Department of Medicine, Duke University Medical Center, Durham, NC, USA. piant001@mc.duke.edu |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
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 |
| Grant Support | |
ID/Acronym/Agency:
|
R01 HL090679-01A1/HL/NHLBI NIH HHS; R01 HL090679-03/HL/NHLBI NIH HHS; R01 HL090679-04/HL/NHLBI NIH HHS; R01 HL096979/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/DNA, Mitochondrial; 0/NF-E2-Related Factor 2; 0/Nrf1 protein, mouse; 0/Nuclear Respiratory Factor 1; 0/RNA, Messenger; 630-08-0/Carbon Monoxide; EC 1.14.99.3/Heme Oxygenase-1; EC 2.7.11.1/Akt1 protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
| Comments/Corrections | |
Comment In:
|
Circ Res. 2008 Nov 21;103(11):1191-3
[PMID:
19028915
]
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Angiotensin(1-7) blunts hypertensive cardiac remodeling by a direct effect on the heart.
Next Document: Stim1 and Orai1 mediate CRAC currents and store-operated calcium entry important for endothelial cel...