Protein kinase G increases antioxidant function in lung microvascular endothelial cells by inhibiting the c-Abl tyrosine kinase

Oxidant injury contributes to acute lung injury (ALI). We previously reported that activation of protein kinase GI (PKGI) posttranscriptionally increased the key antioxidant enzymes catalase and glutathione peroxidase 1 (Gpx-1) and attenuated oxidant-induced cytotoxicity in mouse lung microvascular...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2014-03, Vol.306 (6), p.C559-C569
Main Authors: Stephens, R Scott, Servinsky, Laura E, Rentsendorj, Otgonchimeg, Kolb, Todd M, Pfeifer, Alexander, Pearse, David B
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - physiology
Acute Lung Injury - metabolism
Animals
Antioxidants
Apoptosis - drug effects
Atrial Natriuretic Factor - metabolism
Benzamides - pharmacology
Catalase - metabolism
Cells
Cells, Cultured
Cyclic GMP - analogs & derivatives
Cyclic GMP - metabolism
Cyclic GMP - pharmacology
Cyclic GMP-Dependent Protein Kinases - drug effects
Cyclic GMP-Dependent Protein Kinases - genetics
Cyclic GMP-Dependent Protein Kinases - metabolism
Endothelial Cells - metabolism
Enzyme Activation
Glutathione Peroxidase - metabolism
Hydrogen Peroxide - metabolism
Imatinib Mesylate
Kinases
Lung - cytology
Lung - metabolism
Lungs
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidation-Reduction - drug effects
Physiology
Piperazines - pharmacology
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-abl - antagonists & inhibitors
Proto-Oncogene Proteins c-abl - metabolism
Pyrimidines - pharmacology
RNA, Messenger - biosynthesis
Signal Transduction - drug effects
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Summary:Oxidant injury contributes to acute lung injury (ALI). We previously reported that activation of protein kinase GI (PKGI) posttranscriptionally increased the key antioxidant enzymes catalase and glutathione peroxidase 1 (Gpx-1) and attenuated oxidant-induced cytotoxicity in mouse lung microvascular endothelial cells (MLMVEC). The present studies tested the hypothesis that the antioxidant effect of PKGI is mediated via inhibition of the c-Abl tyrosine kinase. We found that activation of PKGI with the cGMP analog 8pCPT-cGMP inhibited c-Abl activity and decreased c-Abl expression in wild-type but not PKGI(-/-) MLMVEC. Treatment of wild-type MLMVEC with atrial natriuretic peptide also inhibited c-Abl activation. Moreover, treatment of MLMVEC with the c-Abl inhibitor imatinib increased catalase and GPx-1 protein in a posttranscriptional fashion. In imatinib-treated MLMVEC, there was no additional effect of 8pCPT-cGMP on catalase or GPx-1. The imatinib-induced increase in antioxidant proteins was associated with an increase in extracellular H2O2 scavenging by MLMVEC, attenuation of oxidant-induced endothelial barrier dysfunction, and prevention of oxidant-induced endothelial cell death. Finally, in the isolated perfused lung, imatinib prevented oxidant-induced endothelial toxicity. We conclude that cGMP, through activation of PKGI, inhibits c-Abl, leading to increased key antioxidant enzymes and resistance to lung endothelial oxidant injury. Inhibition of c-Abl by active PKGI may be the downstream mechanism underlying PKGI-mediated antioxidant signaling. Tyrosine kinase inhibitors may represent a novel therapeutic approach in oxidant-induced ALI.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00375.2012