Protein Targets of Monocrotaline Pyrrole in Pulmonary Artery Endothelial Cells

A single administration of monocrotaline to rats results in pathologic alterations in the lung and heart similar to human pulmonary hypertension. In order to produce these lesions, monocrotaline is oxidized to monocrotaline pyrrole in the liver followed by hematogenous transport to the lung where it...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-09, Vol.275 (37), p.29091-29099
Main Authors: Lamé, M W, Jones, A D, Wilson, D W, Dunston, S K, Segall, H J
Format: Article
Language:English
Subjects:
Actins - metabolism
Adult
Amino Acid Sequence
Autoradiography
Cells, Cultured
DNA - metabolism
Endothelium, Vascular - metabolism
Female
Galectin 1
Hemagglutinins - metabolism
Humans
Mass Spectrometry
Molecular Sequence Data
Monocrotaline - analogs & derivatives
Monocrotaline - metabolism
Peptide Mapping
Protein Disulfide-Isomerases - metabolism
Pulmonary Artery - metabolism
Tropomyosin - metabolism
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Summary:A single administration of monocrotaline to rats results in pathologic alterations in the lung and heart similar to human pulmonary hypertension. In order to produce these lesions, monocrotaline is oxidized to monocrotaline pyrrole in the liver followed by hematogenous transport to the lung where it injures pulmonary endothelium. In this study, we determined specific endothelial targets for 14 C-monocrotaline pyrrole using two-dimensional gel electrophoresis and autoradiographic detection of protein metabolite adducts. Selective labeling of specific proteins was observed. Labeled proteins were digested with trypsin, and the resulting peptides were analyzed using matrix-assisted laser desorption ionization mass spectrometry. The results were searched against sequence data bases to identify the adducted proteins. Five abundant adducted proteins were identified as galectin-1, protein-disulfide isomerase, probable protein-disulfide isomerase (ER60), β- or γ-cytoplasmic actin, and cytoskeletal tropomyosin (TM30-NM). With the exception of actin, the proteins identified in this study have never been identified as potential targets for pyrroles, and the majority of these proteins have either received no or minimal attention as targets for other electrophilic compounds. The known functions of these proteins are discussed in terms of their potential for explaining the pulmonary toxicity of monocrotaline.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M001372200