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

Publication ,  Journal Article
Piantadosi, CA; Carraway, MS; Babiker, A; Suliman, HB
Published in: Circ Res
November 21, 2008

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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Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

November 21, 2008

Volume

103

Issue

11

Start / End Page

1232 / 1240

Location

United States

Related Subject Headings

  • RNA, Messenger
  • Proto-Oncogene Proteins c-akt
  • Promoter Regions, Genetic
  • Polymerase Chain Reaction
  • Nuclear Respiratory Factor 1
  • NF-E2-Related Factor 2
  • Myocytes, Cardiac
  • Mitochondria, Heart
  • Mice, Knockout
  • Mice, Inbred C57BL
 

Citation

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Piantadosi, C. A., Carraway, M. S., Babiker, A., & Suliman, H. B. (2008). Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res, 103(11), 1232–1240. https://doi.org/10.1161/01.RES.0000338597.71702.ad
Piantadosi, Claude A., Martha Sue Carraway, Abdelwahid Babiker, and Hagir B. Suliman. “Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1.Circ Res 103, no. 11 (November 21, 2008): 1232–40. https://doi.org/10.1161/01.RES.0000338597.71702.ad.
Piantadosi CA, Carraway MS, Babiker A, Suliman HB. Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res. 2008 Nov 21;103(11):1232–40.
Piantadosi, Claude A., et al. “Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1.Circ Res, vol. 103, no. 11, Nov. 2008, pp. 1232–40. Pubmed, doi:10.1161/01.RES.0000338597.71702.ad.
Piantadosi CA, Carraway MS, Babiker A, Suliman HB. Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res. 2008 Nov 21;103(11):1232–1240.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

November 21, 2008

Volume

103

Issue

11

Start / End Page

1232 / 1240

Location

United States

Related Subject Headings

  • RNA, Messenger
  • Proto-Oncogene Proteins c-akt
  • Promoter Regions, Genetic
  • Polymerase Chain Reaction
  • Nuclear Respiratory Factor 1
  • NF-E2-Related Factor 2
  • Myocytes, Cardiac
  • Mitochondria, Heart
  • Mice, Knockout
  • Mice, Inbred C57BL