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

@article{citeulike:4617070, 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 H2O2 production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3{beta}, 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. 10.1161/01.RES.0000338597.71702.ad}, author = {Piantadosi, Claude A. and Carraway, Martha S. and Babiker, Abdelwahid and Suliman, Hagir B.}, citeulike-article-id = {4617070}, citeulike-linkout-0 = {http://dx.doi.org/10.1161/01.RES.0000338597.71702.ad}, citeulike-linkout-1 = {http://circres.ahajournals.org/content/103/11/1232.abstract}, citeulike-linkout-2 = {http://circres.ahajournals.org/content/103/11/1232.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/18845810}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=18845810}, doi = {10.1161/01.RES.0000338597.71702.ad}, journal = {Circ Res}, keywords = {ho-1, mitochondrial\_biogenesis, nrf-1, nrf2}, month = {November}, number = {11}, pages = {1232--1240}, posted-at = {2009-05-24 06:18:03}, priority = {3}, title = {Heme Oxygenase-1 Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of Nuclear Respiratory Factor-1}, url = {http://dx.doi.org/10.1161/01.RES.0000338597.71702.ad}, volume = {103}, year = {2008} }

TY - JOUR ID - citeulike:4617070 L3 - citeulike-article-id:4617070 N2 - 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-3{beta}, 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. 10.1161/01.RES.0000338597.71702.ad IS - 11 JF - Circ Res EP - 1240 TI - Heme Oxygenase-1 Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of Nuclear Respiratory Factor-1 VL - 103 SP - 1232 KW - ho-1 KW - mitochondrial_biogenesis KW - nrf-1 KW - nrf2 AU - Piantadosi, Claude AU - Carraway, Martha AU - Babiker, Abdelwahid AU - Suliman, Hagir PY - 2008/11/21/ UR - http://dx.doi.org/10.1161/01.RES.0000338597.71702.ad ER -