Heme Oxygenase-1 Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of Nuclear Respiratory Factor-1

• Published in: Circulation research Vol. 103; no. 11; pp. 1232 - 1240
• Main Authors: Piantadosi, Claude A, Carraway, Martha Sue, Babiker, Abdelwahid, Suliman, Hagir B
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 21.11.2008; Lippincott Williams & Wilkins
• Subjects: Animals; Biological and medical sciences; Carbon Monoxide - therapeutic use; DNA, Mitochondrial - genetics; Fundamental and applied biological sciences. Psychology; Genes, Reporter; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Heart - physiology; Myocytes, Cardiac - physiology; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - physiology; Nuclear Respiratory Factor 1 - genetics; Polymerase Chain Reaction; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt - deficiency; Proto-Oncogene Proteins c-akt - genetics; RNA, Messenger - genetics; Vertebrates: cardiovascular system; Vertebrata; Mitochondria; Mammalia; nuclear respiratory factor-1; mitochondria■ heme oxygenase■ carbon monoxide; Heme; NF-E2-related factor 2; Circulatory system; Carbon monoxide; Nuclear respiratory factor
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000338597.71702.ad

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 H2O2 production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3β, 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.