© 2000 American Heart Association, Inc.
Editorial |
Lipoprotein Effects on the Vessel Wall
From the Department of Biomedical Sciences, University of California, Riverside, Calif.
Correspondence to Michael B. Stemerman, Division of Biomedical Sciences, B605 Statistics Road, University of California, Riverside, CA 92521-0121. E-mail michael.stemerman{at}ucr.edu
Key Words: lipoproteins • VLDL • LDL • HDL • endothelium
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Introduction |
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 Top Introduction References |
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Accumulation of lipids within the arterial wall is a distinguishing characteristic of the atherosclerotic lesion and is seen in virtually all stages of plaque development. This process is directly correlated with the serum level of some lipids, especially cholesterol, LDL, and other lipoprotein particles. In contrast, an increased serum level of HDL is protective against plaque formation. Evidence has steadily accumulated showing that HDL acts as a "sink" for cholesterol, presumably removing it from tissue. In any discussion of trafficking of materials between blood and the arterial wall, the endothelium must be considered pivotal because of its critical location at the junction between blood and blood vessel. Penetration of lipoproteins into the arterial wall has been shown both quantitatively and qualitatively in experimental animal models. Areas of lipid accumulation appear at localized sites along the arterial lumen in these animal models, consistent with the focal nature of plaque development in humans. The mechanism for the predilection of some localized areas to accumulate plaque has been under debate for a considerable time and is likely multifactorial. In some instances, this process seems related to a focal transient loosing of the tight association between adjoining endothelial cells (ECs). In these areas, there may be easy access to underlying vascular tissue. However, because such gaps appear only occasionally, it is likely that some ECs are actively involved in the accumulation of lipids.1 These topics are at the center of the study by Rutledge et al2 described in this issue of Circulation Research.
In the present study, VLDL was fluorescently labeled and perfused into rat arteries. Attachment of VLDL at the arterial surface was modest, but with the addition of lipoprotein lipase and subsequent VLDL lipolysis, there was accumulation of lipids in the arterial wall in focal areas, or "lakes." After addition of HDL, the lipid-lake accumulation was ameliorated. It seems that HDL acts by both interfering with endothelial permeability and increasing lipid removal rate from the arterial wall. The implication of the former observation is that the permeability of endothelium can be modified by its milieu, and of the latter is that HDL is actively involved in the removal of lipids from tissue. The study provides ex vivo evidence of the ability of HDL to remove lipids from a cellular deposition site and confirms in vitro reports gathered from cell culture studies. The study is particularly important because the site modified by HDL is the arterial wall.
The hypothesis that atherosclerotic progression can be reduced by either improving the barrier function of the arterial wall or modifying blood lipoprotein concentration is the basis of a great deal of current preventative research. Risk factors for atherosclerosis, such as hypertension, smoking, mechanical injury, dense LDL, and genetic predisposition, may affect the barrier function of the arterial wall, predisposing to atherosclerosis. The study by Rutledge et al2 focuses on the modifications of VLDL by lipoprotein lipase and HDL and their influence on the arterial wall and endothelial function.
The concept that alteration in EC function may play a pivotal role in the pathobiology of atherogenesis has been the subject of numerous investigations. Consequently, many of the responses of these cells to stimuli, both physiological and nonphysiological, have begun to provide a mechanistic motif for understanding intracellular EC reaction pathways. With the current hypothesis of atherosclerotic plaque formation centering on the roles of circulating lipoproteins, an understanding of how these lipoproteins affect EC function has begun to emerge. Such studies may not only convey insight into the pathogenesis of plaque formation but also provide important therapeutic implications.
Triglyceride-rich lipoproteins, including VLDL,
chylomicrons, and their remnants, are acknowledged as
cardiovascular disease risk factors, and studies have
implicated VLDL pathogenically in atherosclerosis. For
example, triglyceride-rich remnants have been shown to
impair vasorelaxation,3 and plasma
triglyceride levels show a direct correlation with
plasminogen activator inhibitor
(PAI-1) levels. Incubation of ECs with VLDL induces the synthesis of
PAI-1. Because elevated PAI-1 levels may interfere with
fibrinolysis and therefore predispose to excessive
thrombosis, high-serum VLDL levels may play a role in the development
of thrombotic disorders and cardiovascular disease.
Hence, investigations have been carried out to understand the mechanism
of this effect. Studies using HepG2 cells have investigated the
intracellular signaling pathway induced by VLDL exposure.4
VLDL seems to induce protein kinase C activity, resulting in activation
of mitogen-activated protein kinase. Studies carried out in ECs
indicate that VLDL can also induce nuclear factor-
B
(NF-B),5 a transcription factor that has been shown to
play an important role in the phenotypic modulation of ECs to a
proinflammatory condition. When rats were infused with VLDL, there
ensued an increase in expression of RelA, a component of NF-B,
and an induction of cell adhesion molecules in the arterial
endothelium. Thus, evidence is accumulating that
VLDL directly affects the endothelium, which may
help explain why VLDL is proatherogenic.
HDL seems to protect against plaque formation.6 This
observation has been documented in both experimental animal studies and
human epidemiological investigations. Animal studies describe
protection against the development of lipid deposits when HDL is
abundant in the plasma. Rutledge et al2 provide an
additional demonstration of the effectiveness of HDL in protecting
against plaque formation by showing that HDL can remove lipid buildup
from the vessel. Cell culture studies have examined the salutary effect
of this lipoprotein on the endothelium. To understand
the potential cellular effect of HDL as a vascular protective agent,
ECs were incubated with HDL during exposure to a potent inducer of EC
dysfunction, tumor necrosis factor-
(TNF-).7 HDL
inhibited TNF-–induced expression of adhesion molecules, including
vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and
intercellular cell adhesion molecule-1 (ICAM-1). TNF- is a
well-recognized activator of ECs and seems to have its
primary effect in upregulating adhesion molecule expression by
induction of NF-B. However, the ability of HDL to moderate the
TNF- effect on ECs may be caused by enhancement of Cox-2 expression.
By inducing this enzyme, ECs exposed to HDL produce an abundance of
prostacyclin, which is recognized for its ability to inhibit leukocyte
function. Thus, HDL can modulate a potent activator of ECs
and TNF-; and interestingly, the mechanism seems to be independent
of the transcriptional regulation of NF-B.
LDL has been shown to have a strong correlation with atherosclerotic vascular disease. How LDL is handled by the blood vessel is a major concern for understanding arterial wall plaque development. Elevated LDL levels are associated with a lack of vasorelaxation.8 With a rapid decrease in the serum level of LDL using apheresis, vascular reactivity in humans can be restored rapidly.9 The endothelial response to LDL has been examined using cell culture. The EC phenotype can be modulated by LDL, especially when the concentrations of LDL in the culture medium are similar to those identified with the development of atherosclerosis.
LDL has numerous effects on the endothelium, including
effects on PAI-1,10 arachidonate
metabolism,11 and induction of adhesion
molecule expression. Of particular interest to the inflammatory
component of plaque development is the upregulation of both
ICAM-112 and VCAM-1.13 In examining the
mechanism underlying this modulation, it has been determined that
exposure of ECs to LDL causes the rapid activation of
Ras.14 Ras activation leads to induction of the signaling
cascade that activates JNK and the expression of AP-1, which in
turn can upregulate ICAM-1. In contrast to VLDL-induced signaling,
NF-B seems to have little, if any, role in the induction of adhesion
molecule formation by LDL. Indeed, LDL is the only
physiological substance known to behave in this
fashion. Recent studies have pursued this finding and indicate that
most of this activation resides in the free-cholesterol
component of LDL.15 If this is the case, it can be
hypothesized that cholesterol is a biologically active
molecule carried by LDL, which initiates cellular activation. One of
the implications of this notion is the likelihood not only that LDL and
serum cholesterol are risk factors for developing
atherosclerosis, but also that lipids can act directly
as atherogenic factors. Hence, our ability to comprehensively
understand the varying roles of lipoproteins as they affect the
arterial vasculature has major ramifications for
understanding and controlling atherosclerosis.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Nielsen LB. Transfer of low density lipoprotein into the arterial wall and risk of atherosclerosis. Atherosclerosis. 1996;123:1–15.[Medline] [Order article via Infotrieve]
2.
Rutledge JC, Mullick AE, Gardner G, Goldberg IJ.
Direct visualization of lipid deposition and reverse lipid transport in
a perfused artery: roles of VLDL and HDL. Circ Res. 2000;86:768–773.
3. Doi H, Kugiyama K, Ohgushi M, Sugiyama S, Matsumura T, Ohta Y, Nakano T, Nakajima K, Yasue H. Remnants of chylomicron and very low density lipoprotein impair endothelium-dependent vasorelaxation. Atherosclerosis. 1998;137:341–349.[Medline] [Order article via Infotrieve]
4.
Banfi C, Mussoni L, Ris P, Cattaneo MG, Vicentini L,
Battaini F, Galli C, Tremoli E. Very low density lipoprotein-mediated
signal transduction and plasminogen activator
inhibitor type 1 in cultured HepG2 cells. Circ
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5.
Dichtl W, Nilsson L, Goncalves I, Ares MP, Banfi C,
Calara F, Hamsten A, Eriksson P, Nilsson J. Very low-density
lipoprotein activates nuclear factor-B in
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6. Tall AR. An overview of reverse cholesterol transport. Eur Heart J. 1998;19(suppl A):A31–A35.
7.
Cockerill GW, Saklatvala J, Ridley SH, Yarwood H,
Miller NE, Oral B, Nithyanathan S, Taylor G, Haskard DO. High-density
lipoproteins differentially modulate cytokine-induced
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9. Mellwig KP, Baller D, Gleichmann U, Moll D, Betker S, Weise R, Notohamiprodjo G. Improvement of coronary vasodilatation capacity through single LDL apheresis. Atherosclerosis. 1998;139:173–178.[Medline] [Order article via Infotrieve]
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Levin EG, Miles LA, Fless GM, Scanu AM, Baynham P,
Curtiss LK, Plow EF. Lipoproteins inhibit the secretion of tissue
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11. Pritchard KA Jr, Wong PY, Stemerman MB. Atherogenic concentrations of low-density lipoprotein enhance endothelial cell generation of epoxyeicosatrienoic acid products. Am J Pathol. 1990;136:1383–1391.[Abstract]
12.
Smalley DM, Lin JH, Curtis ML, Kobari Y, Stemerman MB,
Pritchard KAJ. Native LDL increases endothelial cell
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14. Zhu Y, Liao H, Wang N, Verna L, Ma K-S, Zhang S-X, Liao JK, Stemerman MB. Low-density lipoprotein activates Ras-dependent signaling pathway in human endothelial cells. Circulation. 1999;100(suppl I):I-693. Abstract.
15. Yuan Y, Wang N, Zhu Y, Verna L, Stemerman MB. Cholesterol causes human vascular endothelial cell (EC) activation. FASEB J.. 2000;14:A414. Abstract 306.28.
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