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J. Biol. Chem., Vol. 275, Issue 37, 29091-29099, September 15, 2000
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From the 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 14C-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),
Protein Targets of Monocrotaline Pyrrole in Pulmonary Artery
Endothelial Cells*
,
Department of Molecular Biosciences and the
¶ Department of Pathology, Microbiology, and Immunology, School of
Veterinary Medicine, University of California,
Davis, California 95616 and the § Department of
Chemistry and Intercollege Mass Spectrometry Center, 152 Davey
Laboratory, The Pennsylvania State University,
University Park, Pennyslvania 16802
- or 
-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.
*
This work was supported by National Institutes of Health
Grant HL48411 (to H. J. S.). The mass spectrometer was
purchased in part with Grant RR11318 from the National Institutes of
Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Molecular
Biosciences, School of Veterinary Medicine, University of California, Davis, One Shields Ave., Davis, CA 95616. Tel.: 530-752-6173; Fax:
530-752-4698; E-mail: HJSegall@ucdavis.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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