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

CA Piantadosi, MS Carraway, A Babiker… - Circulation …, 2008 - Am Heart Assoc
CA Piantadosi, MS Carraway, A Babiker, HB Suliman
Circulation research, 2008Am Heart Assoc
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 …
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.
Am Heart Assoc