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Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1.

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.
AuthorsClaude A Piantadosi, Martha Sue Carraway, Abdelwahid Babiker, Hagir B Suliman
JournalCirculation research (Circ Res) Vol. 103 Issue 11 Pg. 1232-40 (Nov 21 2008) ISSN: 1524-4571 [Electronic] United States
PMID18845810 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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
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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