© 1998 American Heart Association, Inc.
Brief Reviews |
Sphingolipids in Atherosclerosis and Vascular Biology
From the Lipid Research Atherosclerosis Division, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Subroto Chatterjee, Lipid Research Atherosclerosis Division, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N Wolfe St, CMSC 6-124, Baltimore, MD 21287-3654. E-mail chatter{at}welchlink.welch.jhu.edu
Abstract
Abstract—Sphingolipids and their
metabolic products are now known to have
second-messenger functions in a variety of cellular signaling pathways.
Lactosylceramide (LacCer), a glycosphingolipid (GSL) present in
vascular cells such as endothelial cells, smooth muscle
cells, macrophages, neutrophils, platelets, and monocytes,
contributes to atherosclerosis. Large amounts of LacCer
accumulate in fatty streaks, intimal plaque, and calcified intimal
plaque, along with oxidized low density lipoproteins (Ox-LDLs), growth
factors, and proinflammatory cytokines. A possible role for
LacCer in vascular cell biology was suggested when this GSL was found
to stimulate the proliferation in vitro of aortic smooth muscle cells
(ASMCs). A further link of LacCer in atherosclerosis
was uncovered by the finding that Ox-LDLs stimulated specifically the
biosynthesis of LacCer. Ox-LDL–stimulated endogenous
synthesis of LacCer by activation of
UDP-Gal:GlcCer,ß1-4galtransferase (GalT-2) is an early step in this
signaling pathway. In turn, LacCer serves as a lipid second messenger
that orchestrates a signal transduction pathway, ultimately leading to
cell proliferation. This signaling pathway includes LacCer-mediated
activation of NADPH oxidase that produces superoxide. Such superoxide
molecules stimulate the GTP loading of p21ras.
Subsequently, the kinase cascade (Raf-1, Mek2, and p44MAPK
[mitogen-activated protein kinase]) is activated. The
phosphorylated form of p44MAPK translocates
from the cytoplasm to the nucleus and engages in c-fos
expression, proliferating cell nuclear antigen (PCNA) such as cyclin
activation, and cell proliferation takes place. Interestingly,
D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol
(D-PDMP), an inhibitor of GalT-2, can abrogate the
Ox-LDL–mediated activation of GalT-2, the signal kinase cascade noted
above, as well as cell proliferation. Additional studies have revealed
that LacCer mediates the tumor necrosis factor-
(TNF-)–induced
nuclear factor-
B expression and intercellular adhesion molecule
(ICAM-1) expression in vascular endothelial cells via
the redox-dependent transcriptional pathway. LacCer also stimulates the
expression of CD11/CD8, or Mac-1, on the surface of human neutrophils.
Collectively, this phenomenon may contribute to the adhesion of
neutrophils or monocytes to the endothelial cell
surface and thus initiate the process of
atherosclerosis. In addition, the LacCer–mediated
proliferation of ASMCs may contribute to the progression of
atherosclerosis. On the other hand, programmed
cell death (apoptosis) by proinflammatory cytokines
such as TNF-, interleukin-1, and high concentrations of Ox-LDL occur
via activation of a cell membrane–associated neutral sphingomyelinase
(N-SMase). N-SMase hydrolyzes sphingomyelin into ceramide and
phosphocholine. In turn, ceramide or a homologue serves as an important
stress-signaling molecule. Interestingly, an antibody against N-SMase
can abrogate Ox-LDL– and TNF-–induced apoptosis and
therefore may be useful for in vivo studies of apoptosis in
experimental animals. Because plaque stability is an integral aspect of
atherosclerosis management, activation of N-SMase and
subsequent apoptosis may be vital events in the onset of plaque
rupture, stroke, or heart failure. Interestingly, in human liver cells,
N-SMase action mediates the TNF-–induced maturation of the sterol
regulatory-element binding protein. Moreover, a cell-permeable ceramide
can reconstitute the phenomenon above in a sterol-independent fashion.
Such findings may provide new avenues for therapy for patients with
atherosclerosis. The findings described here indicate
an important role for sphingolipids in vascular biology and provide an
exciting opportunity for further research in vascular disease and
atherosclerosis.
Key Words: neutral sphingomyelinase • lipoproteins • cell proliferation • signal transduction • apoptosis
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