Abstract
Background: Hyperhomocysteinemia is recognized as a risk factor for atherosclerotic disease.
However, the mechanism of homocysteine effects on smooth muscle cell proliferation,
which is a hallmark of atherosclerosis, is unknown. The object of this study was to
test the effects of homocysteine on smooth muscle cell proliferation, and to examine
the mitogen-activated protein (MAP) kinases, extracellular signal-regulated protein
kinase 1 and 2, that are known to be involved in cell proliferation. Methods: For the proliferation study, bovine aortic smooth muscle cells (BASMC, 10,000/well)
were allowed to grow for 2 days before 2 mmol/L D,L -homocysteine was added for 2, 4, 6, and 8 days to simulate the clinical hyperhomocysteinemic
condition. For the MAP kinase study, quiescent BASMC were exposed to 2 mmol/L D,L -homocysteine for 1.5, 5, 10, 20, 30, and 60 minutes, and the active forms of MAP
kinase were detected with Western immunoblotting. The degree of phosphorylation of
MAP kinase was determined by densitometry. Results:D,L -homocysteine stimulated BASMC proliferation by 20% by day 8. MAP kinase phosphorylation
was activated as much as six fold by D,L -homocysteine, with a peak at 30 minutes. PD98059, an inhibitor of MAP kinase phosphorylation,
inhibited the homocysteine-induced MAP kinase phosphorylation and attenuated the increase
in BASMC proliferation. Conclusions: These data are consistent with the hypothesis that D,L -homocysteine stimulation of BASMC proliferation involves MAP kinase activation.
(Surgery 2000;128: 59-66.)
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Article info
Publication history
Accepted:
February 13,
2000
Footnotes
*Supported by grants to B. E. S. from the National Institutes of Health (R01-47345), the Veterans Administration Merit Review Board, and the American Heart Association (National).
**Reprint requests: Bauer E. Sumpio, MD, PhD, Department of Vascular Surgery, Yale University School of Medicine, FMB 137, 333 Cedar St, New Haven, CT 06510.
Identification
Copyright
© 2000 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
