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(Received for publication, October 22, 1996, and in revised form, March 19, 1997)
From The Johns Hopkins University School of Medicine, Lipid
Research Atherosclerosis Unit, Department of Pediatrics,
Baltimore, Maryland 21287-3654
Previously, our laboratory reported that
lactosylceramide (LacCer) stimulated human aortic smooth muscle cell
proliferation via specific activation of p44 mitogen-activated protein
kinase (MAPK) in the p21ras/Raf-1/MEK2 pathway and induced
expression of the transcription factor c-fos downstream to
the p44 MAPK signaling cascade (Bhunia A. K., Han, H., Snowden, A., and
Chatterjee S. (1996) J. Biol. Chem. 271, 10660-10666). In the present study, we explored the role of free
oxygen radicals in LacCer-mediated induction of cell proliferation.
Superoxide levels were measured by the lucigenin chemiluminescence
method, MAPK activity was measured by immunocomplex kinase assays, and
Western blot analysis and c-fos expression were measured by
Northern blot assay. We found that LacCer (10 µM)
stimulates endogenous superoxide production (7-fold compared with
control) in human aortic smooth muscle cells specifically by activating
membrane-associated NADPH oxidase, but not NADH or xanthine oxidase.
This process was inhibited by an inhibitor of NADPH oxidase,
diphenylene iodonium (DPI), and by antioxidants, N-acetyl-L-cysteine (NAC) or pyrrolidine
dithiocarbamate. NAC and DPI both abrogated individual steps in the
signaling pathway leading to cell proliferation. For example, the
p21ras·GTP loading, p44 MAPK activity, and induction of
transcription factor c-fos all were inhibited by NAC and
DPI as well as an antioxidant pyrrolidine dithiocarbamate or reduced
glutathione (GSH). In contrast, depletion of GSH by
L-buthionine (S,R)-sulfoximine
up-regulated the above described signaling cascade.
In sum, LacCer, by virtue of activating NADPH oxidase, produces
superoxide (a redox stress signaling molecule), which mediates cell
proliferation via activation of the kinase cascade. Our findings may
explain the potential role of LacCer in the pathogenesis of atherosclerosis involving the proliferation of aortic smooth muscle cells.
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