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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes
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Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes

机译：一氧化碳通过中断MAPK驱动的早期生长反应1基因及其下游靶基因的表达来拯救缺血性肺

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摘要

Carbon monoxide (CO), an endogenous cytoprotective product of heme oxygenase type-1 regulates target thrombotic and inflammatory genes in ischemic stress. Regulation of the gene encoding early growth response 1 (Egr-1), a potent transcriptional activator of deleterious thrombotic and inflammatory cascades, may govern CO-mediated ischemic lung protection. The exact signaling mechanisms underlying CO-mediated cytoprotection are not well understood. In this study we tested the hypothesis that inhibition of mitogen-activated protein kinase-dependent Egr-1 expression may be pivotal in CO-mediated ischemic protection. In an in vivo isogeneic rat lung ischemic injury model, inhaled CO not only diminished fibrin accumulation and leukostasis and improved gas exchange and survival but also suppressed extracellular signal-regulated kinase (ERK) activation, Egr-1 expression, and Erg DNA-binding activity in lung tissue. Additionally, CO-mediated inhibition of Egr-1 reduced expression of target genes, such as tissue factor, serpine-1, interleukin-1, and TNF-alpha. However, CO failed to inhibit serpine-1 expression after unilateral lung ischemia in mice null for the Egr-1 gene. In RAW macrophages in vitro, hypoxia-induced Egr-1 mRNA expression was ERK-dependent, and CO-mediated suppression of ERK activation resulted in Egr-1 inhibition. Furthermore, CO suppression of ERK phosphorylation was reversed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but was insensitive to cAMP-dependent protein kinase A inhibition with H89 and NO synthase inhibition with L-nitroarginine methyl ester. This finding indicates that CO suppresses ERK in a cGMP-dependent but cAMP/protein kinase A- and NO-independent manner. Together, these data identify a unifying molecular mechanism by which CO interrupts proinflammatory and prothrombotic mediators of ischemic injury.
机译：一氧化碳（CO）是1型血红素加氧酶的内源性细胞保护产物，可调节缺血性应激中的靶血栓和炎症基因。编码早期生长应答1（Egr-1）的基因（一种有害的血栓形成和炎症级联反应的有效转录激活因子）的调控可能控制CO介导的缺血性肺保护。 CO介导的细胞保护基础的确切信号转导机制尚不清楚。在这项研究中，我们测试了一种假设，即有丝分裂原激活的蛋白激酶依赖性Egr-1表达的抑制可能在CO介导的缺血保护中起关键作用。在体内同基因大鼠肺缺血性损伤模型中，吸入的CO不仅减少了纤维蛋白的积聚和白细胞减少，改善了气体交换和存活，还抑制了细胞外信号调节激酶（ERK）激活，Egr-1表达和Erg DNA结合活性在肺组织中。此外，CO介导的Egr-1抑制作用会降低目标基因的表达，例如组织因子，serpine-1，interleukin-1和TNF-alpha。然而，在Egr-1基因无效的小鼠单侧肺缺血后，CO不能抑制serpine-1的表达。在体外RAW巨噬细胞中，缺氧诱导的Egr-1 mRNA表达是ERK依赖性的，CO介导的ERK激活抑制导致Egr-1抑制。此外，鸟苷酸环化酶抑制剂1H- [1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮可逆转CO对ERK磷酸化的抑制作用，但对c89依赖性蛋白激酶A对H89和H89的抑制作用不敏感用L-硝基精氨酸甲酯抑制NO合酶。该发现表明CO以cGMP依赖性但cAMP /蛋白激酶A依赖性和NO依赖性的方式抑制ERK。这些数据共同确定了一个统一的分子机制，CO可以通过这种分子机制中断缺血性损伤的促炎和血栓形成介质。

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