Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1.
Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1.
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DOI：
10.1161/01.res.0000338597.71702.ad
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发表时间：
2008-11-21
影响因子：
20.1
通讯作者：
Suliman HB
中科院分区：
文献类型：
--
作者：
Piantadosi CA;Carraway MS;Babiker A;Suliman HB
血红素加氧酶 (HO)-1 是一种保护性抗氧化酶，可防止心肌细胞凋亡，例如在进行性心肌病期间。在这里，我们通过证明小鼠心脏中的 HO-1 活性通过诱导 NF-E2 相关因子 (Nrf)2 基因表达和核转位来刺激双基因组线粒体生物发生程序，确定了 HO-1 保护机制的一个基本方面。 Nrf2 上调 HO-1 的 mRNA、蛋白质和活性以及核呼吸因子 (NRF)-1 的 mRNA 和蛋白质。从机制上讲，在心肌细胞中，HO-1 过表达产生的内源性一氧化碳 (CO) 会刺激超氧化物歧化酶-2 上调和线粒体 H2O2 产生，从而激活 Akt/PKB。 Akt 使糖原合成酶激酶 3β 失活，从而允许 Nrf2 核易位并占据 NRF-1 启动子中的 4 个抗氧化反应元件 (ARE)。随后核 NRF-1 蛋白的积累导致线粒体生物发生的基因激活，从而对抗心脏毒性蒽环类化疗药物阿霉素引起的细胞凋亡和坏死。在心脏细胞中，Akt 沉默会加剧阿霉素诱导的细胞凋亡，体内 CO 可以拯救野生型小鼠，但不能拯救阿霉素心肌病的 Akt1−/− 小鼠。这些发现将通过 Nrf2 和 Akt 的 HO-1/CO 信号转导至线粒体生物发生的心肌转录程序，为靶向线粒体 CO 治疗提供了基本原理，并将心脏线粒体体积扩张与异生素和抗氧化细胞防御的诱导网络联系起来。
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 cardiotoxic 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.