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Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its
Snigdha Mishra1, Tomoyuki Fujita, Vibha N Lama
1Department of Internal Medicine, University of Michigan, 3119N Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Abstract:
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.
Insights
Carbon monoxide (CO) protects lungs during ischemic stress by inhibiting the early growth response 1 (Egr-1) gene. This pathway involves guanylate cyclase and suppresses inflammatory and thrombotic gene expression.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Carbon monoxide (CO) is an endogenous cytoprotective molecule derived from heme oxygenase-1.
- CO regulates genes involved in thrombotic and inflammatory responses during ischemic stress.
- The precise mechanisms of CO-mediated cytoprotection, particularly in ischemic lung injury, require further elucidation.
Purpose of the Study:
- To investigate the hypothesis that CO-mediated ischemic lung protection involves the inhibition of mitogen-activated protein kinase-dependent early growth response 1 (Egr-1) expression.
- To identify the specific signaling pathways through which CO exerts its cytoprotective effects in ischemic lung injury.
Main Methods:
- Utilized an in vivo rat lung ischemic injury model and in vitro RAW macrophage experiments.
- Administered inhaled CO and employed molecular techniques to assess gene expression, protein activation, and DNA-binding activity.
- Investigated the roles of extracellular signal-regulated kinase (ERK), Egr-1, guanylate cyclase, cAMP-dependent protein kinase A, and nitric oxide synthase.
Main Results:
- Inhaled CO reduced fibrin accumulation, leukostasis, and improved gas exchange and survival in rats with ischemic lung injury.
- CO suppressed ERK activation, Egr-1 expression, and Egr-1 DNA-binding activity in lung tissue.
- CO-mediated Egr-1 inhibition led to reduced expression of target genes including tissue factor, serpine-1, interleukin-1, and TNF-alpha.
- CO's inhibitory effect on Egr-1 was dependent on Egr-1 gene presence and involved a cGMP-dependent, but cAMP/PKA- and NO-independent, suppression of ERK phosphorylation.
Conclusions:
- CO confers protection against ischemic lung injury by inhibiting Egr-1 expression via a cGMP-dependent pathway involving ERK.
- This mechanism effectively interrupts the expression of key proinflammatory and prothrombotic mediators, offering a unifying molecular explanation for CO's cytoprotective role.
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