ARTICLE
INTRODUCTION
Injury of the vascular endothelium is a critical event in the pathogenesis
of atherosclerosis. Importantly, endothelial cells in lesion-prone regions,
where atherosclerotic lesions preferentially develop, are characterised
by increased endothelial cell turn-over rates suggesting a mechanistic
link between endothelial cell turn-over and the susceptibility to atherosclerotic
plaque development [1]. The enhanced endothelial cell turn-over most likely
is secondary to an increase of the physiological kind of cell death, namely
apoptosis. Apoptosis or programmed cell death refers to the morphological
alterations exhibited by "actively" dying cells that include cell shrinkage,
membrane blebbing, chromatin condensation and DNA fragmentation. The present
article will focus on the susceptibility of endothelial cells towards
apoptosis-induction by proatherosclerotic factors and the underlying signalling
events. In addition, the effect of endogenous anti-atherosclerotic factors
on endothelial cell apoptosis are summarised.
APOPTOSIS OF ENDOTHELIAL
CELLS
First evidence that apoptosis can be induced in endothelial cells was
reported up in 1991 by Robaye and coworkers [2], who demonstrated apoptosis
induction by the inflammatory cytokine TNF-alpha. These findings have
been reproduced meanwhile by several groups [3]. If the hypothesis is
correct that endothelial cell apoptosis plays a role in the pathophysiology
of atherosclerosis, proatherosclerotic factors should induce endothelial
cell apoptosis. Indeed, high glucose concentrations mimicking the diabetic
situation have been shown to trigger endothelial cell apoptosis [4]. Furthermore,
oxidized low density lipoprotein, which plays a key role in atherogenesis,
stimulates the endogenous suicide cell death program of endothelial cells
via activation of the caspases [5]. Clinical studies as well as
experimental evidence further suggest a causal pathophysiological role
of increased oxidative stress in the progression of atherosclerosis. Of
note, reactive species are potent inducers of apoptotic endothelial cell
death [6]. Finally, angiotensin II induces apoptosis of endothelial cells
[7]. To summarize, the major risk factors for atherosclerosis such as
high glucose, oxidized low density lipoprotein, angiotensin II as well
as reactive oxygen species promote endothelial cell apoptosis and thereby
may contribute to the initiation of atherosclerotic lesion formation.
Moreover, the bacterial toxin lipopolysaccharide has been shown to trigger
endothelial cell apoptosis suggesting a link between infections and endothelial
cell injury [8].
PROTECTION AGAINST ENDOTHELIAL
CELL APOPTOSIS
Having described the factors contributing to the development of atherosclerosis
which also are potent inducers of endothelial cell death, it remains the
questions whether endogenous anti-atherosclerotic factors prevent endothelial
cell apoptosis.
Shear Stress
The focal nature of atherosclerotic lesion development in areas with
turbulent or low blood flow such as bifurcations indicates that one of
the most potent endogenous anti-atherosclerotic factors seems to be the
laminar blood flow. Laminar shear stress has been shown to completely
prevent apoptosis induction induced by various stimuli. Moreover, a lack
of hemodynamic force has been shown to trigger apoptosis of endothelial
cells [9]. The effect of shear stress on various stimuli suggests the
interference with a common apoptosis signalling event. Indeed, exposure
of HUVEC to laminar flow inhibits the activation of caspase-3, the final
common apoptosis executioner. The inhibition thereby seems to be at least
in part mediated by the shear stress-stimulated release of nitric oxide
[3], which inhibited the caspases cascade via S-nitrosylation of
the essential cysteine residue [3]. In addition, the enhanced anti-oxidative
capacity of endothelial cells induced by shear stress seems to contribute
to the anti-apoptotic effect [6]. In detail, shear stress-induced expression
of Cu/Zn superoxide dismutase [10], the interference with the glutathion
redox system [6] and the nitric oxide release synergistically inhibit
apoptosis induction.
Other anti-apoptotic
factors
Anti-oxidants reveal endothelial-protective effects and have been shown
to prevent endothelial cell apoptosis induced by TNF-alpha, oxidized LDL
and endotoxin [5, 8, 11]. Moreover, the female hormone oestrogen also
inhibits apoptosis induction [12].
Taken together, the fate of the endothelial cell is influenced by various
factors as illustrated in Figure
1. In lesion-protected areas, endothelial cells show a low mitotic
rate and usually remain viable until 20 years thus indicating that apoptosis
is a relatively rare event under physiological conditions. However, endothelial
cells in regions, where the blood flow is low or unsteady, may be susceptible
to pro-inflammatory or pro-atherosclerotic factors, which may initiate
the endothelial cell injury. Importantly, apoptotic endothelial cells
become procoagulant [13]. Thus, apoptosis of endothelial cells may not
only lead to the disturbance of the integrity of the endothelium, but
may further initiate platelet and neutrophil aggregation and thereby amplifying
an inflammatory response. Further studies are necessary to transfer the
in vitro evidences for an important role of endothelial cell apoptosis
in the pathophysiology of atherosclerosis into the in vivo situation.
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