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The etiology of preeclampsia is still
unknown. The 4 hypotheses currently accepted are the placental
ischemia hypothesis, genetic hypothesis, the immune maladaption
and hypothesis of the imbalance between free oxygen radicals and
scavengers in favor of oxidants. At present the most popular
theory is that of oxidative stress, that leads to increased
production of lipid peroxides, thromboxane A2 and decreased
level of prostacyclin. This imbalance triggers endothelial
dysfunction and its clinical manifestation. Scavenging reducing
systems have protective effect in this process.1 This chapter
reviews these oxidative stress and the current status of
reducing systems like Vit. C and E in pre-eclampsia.
One hypothesis receiving a great deal of attention is that
placental and maternal factors converge to generate “oxidative
stress” (an imbalance between oxidant and reducing system or
reducing forces in favor of oxidants), promoting a vicious cycle
of events that compromise the “defensive” vasodilatory,
antiaggregatory, and barrier functioning of the vascular
endothelium. Problems relating to maternal constitution, such as
abnormal lipid metabolism and associated insulin resistance may
be particularly important in this regard.
OXIDANT-ANTIOXIDANT INTERACTIONS:
Free Radicals And Reactive Oxygen Species:
There are comprehensive reviews on interactions between
reactive oxygen species and reducing systems in human health and
disease. A wide spectrum of reactive oxygen species function as
signal transducers in normal physiology but their overproduction
may result in, or is the result of, a number of human health
problems. Overproduction of reactive oxygen species can arise
from a variety of sources, both environmental and metabolic.
Tissue ischemia/hypoxia followed by reperfusion is one
established generator of reactive oxygen species and lipid
peroxidation in vivo. Postischemic reperfusion generation of
reactive oxygen species could be one source of oxidative injury
in placentae of women with preeclampsia.
Recently decreased expression of reducing
systems thioredoxin and glutaredoxin in placentae from
pregnancies with pre-eclampsia and intrauterine growth
restriction have been documented. These studies were carried out
to test a hypothesis that suggests that pre-eclampsia is
associated with inadequate control by the thioredoxin system and
other related reducing systems. Placental tissue from normal
pregnancies (NC), severe pre-eclampsia with fetuses small for
gestational age (SPE), mild pre-eclampsia with fetuses small for
gestational age (MPE) and pregnancies with small fetuses for
gestational age without any sign of pre-eclampsia (IUGR) was
collected immediately after delivery.
Lipid Peroxidation:
Lipid peroxidation has received a great deal of attention in
preeclampsia. The process can be described as oxidative
deterioration of polyunsaturated fatty acids. The primary
products of lipid peroxidation, lipid hydroperoxides, function
in normal physiology. Reactive oxygen species/ reducing system
imbalances can lead to uncontrolled lipid peroxidation.
Oxidative Stress And The Vascular Endothelium:
Research focusing on arteriosclerosis has aptly demonstrated
that the vascular endothelium is prone to damage from reactive
oxygen species. Because vascular endothelial cells interface
with blood, they are exposed to a variety of prooxidants
including heme compounds and reactive species from activated
neutrophils and platelets. Circulating lipids have diverse
effects upon endothelial cell function, and dyslipidemia is
associated with endothelial cell dysfunction. In particular,
there is a considerable interest in the role played by
low-density lipoprotein (LDL) oxidation in endothelial
disturbances. LDL particles can undergo oxidation in vivo and
such modification contributes to arterial lesions in
arteriosclerosis and diabetes. The LDL particles continuously
enter and exit the artery wall. In the sub endothelial
interstitial matrix, LDL, may be exposed more frequently to cell
derived oxidants and at the same time are less protected by
reducing systems relative to circulating LDL. This potential for
prolonged contact between LDL and the cell makes the sub
endothelial space the likely site of LDL oxidation and is one
reason the endothelium is a likely target for oxidized LDL-mediated
disturbances 51-53. As will be discussed later in this chapter,
the appearance of hypertriglyceridemia followed by increased
prevalence of smaller, more oxidation-susceptible LDL particles
might contribute to endothelial dysfunction in preeclampsia.
Continued oxidation is facilitated (primed) by “feed-forward”
interaction of lipid hydroperoxides in the LDL particle with
cell-derived oxidants. These more extensive changes lead to
recognition by the macrophage scavengers and synthesis of
oxidized LDL antibodies.
The deleterious effects of lipid
peroxidation (including peroxidation of LDL) on the vasclature
include inhibition of endothelium-dependent relaxation. Also,
the “oxidative stress theory” of preeclampsia finds indirect
support in that many of the endothelial abnormalities described
in preeclampsia can be reproduced by lipid peroxidation in
experimental system.
PLACENTAL OXIDATIVE STRESS:
The hypothesis that the etiology of preeclampsia is related to
deficient trophoblast invasion and failure of uterine artery
remodeling is well founded. Defective arterial remodeling in
preeclampsia and in intrauterine growth restriction (IUGR)
results in reduced uteroplacental perfusion, which may
predispose to episodes of placental hypoxia or ischemia.
Placental infarcts occur with increased frequency in
preeclampsia, consistent with focal hypoxia/ischemia.
Placental Nitrotyrosine, Xanthine Oxidase, And The Issue Of
Reperfusion Damage:
Tissue hypoxia/ ischemia followed by
reoxygenation can generate reactive oxygen species and lipid
peroxidation in vivo If conjoined with vascular reperfusion,
placental hypoxia /ischemia could result in oxidative damage and
elaboration of cytotoxic reactive oxygen products into the
circulation. However, it is unclear whether placental
postischemic reoxygenation damage occurs in preeclampsia.
Placental trophoblasts produce nitric oxide Preeclampsia and
intrauterine growth restriction are associated with increased
expression of the endothelial isoform of nitric oxide synthase (eNOS)
in the villous vessel endothelium. The role of nitric oxide (NO)
in normal pregnancy and pregnancy complicated with preeclampsia
(PE) and/or intrauterine growth restriction (IUGR) is under
investigations. Nitric Oxide (NO) is a potent vasodilator
released by endothelial cells. It is synthesized by the
catalytic action of the endothelial constitutive nitric oxide
synthase (ecNOS). Moreover, the synthesis of NO in normal human
placental vasculature has already been established and
impairment of the uteroplacental blood flow in pregnancies
complicated by PE and/or IUGR has been demonstrated.
Placental Lipid Peroxidation:
The lipid peroxidation degradation product, malondialdehyde,
is reportedly increased in placental tissue along with decreases
in SOD activity in preeclampsia. In pre-eclampsia, increased
levels of lipid peroxide and decreased SOD activity have been
described in the placenta. Oxidative stress such as occurs in
pre-eclampsia can alter expression of SOD isoforms. Chemical
inhibition of placental glutathione peroxides resulted in
increased production of lipid hydroperoxides and an increase in
the placental thromboxane to prostacyclin output ratio. The
consequences of this altered ratio might include vasospasm with
exacerbation of placental ischemia, increased cell damage, and
increased lipid peroxidation (amplification loop)
DYSLIPIDEMIA AND OXIDATIVE STRESS IN
PREECLAMPSIA:
Dyslipidemia In Preeclampsia:
Super-normal increases in serum triglyceride and free fatty
acids develop as early as 10 weeks’ gestation in women destined
to develop preeclampsia. Nearly 50% of women with preeclampsia
have triglyceride concentrations > 400 mg/ dL. Total cholesterol
and LDL – cholesterol concentrations are usually not different
whereas HDL2 cholesterol is decreased in clinically evident
preeclampsia.
POTENTIAL IMPACT OF DYSLIPIDEMIA ON OXIDATIVE STRESS:
Free fatty acid increases might contribute to endothelial
dysfunction in preeclampsia by several means. The pathogenic
significance of small, dense LDL, and the formation of small,
dense LDL, during normal and preeclamptic pregnancy are
summarized in the next two sections,
Small Dense LDL Phenotype And Its Vascular Consequences:
Metabolic changes producing
hypertriglyceridemia generally shift the spectrum of LDL sub
fractions toward a proportional increase of smaller, denser LDL.
Small, dense LDL particles are relatively depleted of
cholesteryl esters, and enriched in protein. Proportional
increases in small, dense LDL with heightened susceptibility to
oxidative modification may account for part of the increased
cardiovascular risk in individuals with the small, dense LDL
phenotype. The reasons for increased oxidation susceptibility
with decreasing particle size may include proportional
polyunsaturated fatty acid increases and decreased reducing
systems (ubiquinol-10 and/or vitamin) per particle.
Small, Dense LDL In Normal And Pre-eclamptic Pregnancy:
The normal pregnancy rise in plasma triglyceride is
associated with a shift from predominantly large and buoyant LDL
(no pregnancy) to intermediate and small, dense LDL (36 week’s
gestation), with partial reversal by 6 weeks postpartum. LDL
size correlated negatively with triglycerides (R= -0.61,
P<0.01).
Some studies measured the mass of three LDL sub fractions (LDL
–I, II, and III) isolated on the basis of increasing density
from plasma of women with preeclampsia and normal pregnancy.
Preheparin hepatic lipase activity was increased in preeclampsia
plasma that, by hydrolysis of LDL triglycerides, could partially
explain predominance of small, dense LDL in the syndrome.
It is evident that not all women with
preeclampsia exhibit smaller, denser LDL relative to normal
pregnancy. Apart from size differences one component of
pathophysiology in preeclampsia might be abnormal maternal or
placental response to (or handling of) the small, dense LDL may
impart substantial increases in LDL oxidation susceptibility.
The intrinsic susceptibility of isolated LDL to Cu2+ mediated
oxidation is increased in preeclampsia. Whether this is a
function of LDL size shift or some unrelated LDL difference is
presently unclear.
In preeclampsia, however, evidence for the interaction of plasma
lipids, reactive oxygen species, and endothelial cell
dysfunction is largely indirect, In contrast to
arteriosclerosis, for example, there are currently no positive
or negative reports on isolation of oxidized lipids from
vascular tissues in preeclampsia.
LESSONS FROM EXTRACELLULAR REDUCING
SYSTEMS:
Non-enzymatic, low molecular mass reducing systems are the
primary protestants against oxidative damage in the extra
cellular compartment. They protect by reacting with radicals
faster than radicals can react with potential targets and
because anti oxidant radicals formed during electron transfer
are usually less reactive than the initial inciting radical.
Whether a molecule acts as an oxidant or reductant in any given
interaction can often be predicted from tables of standard
one-electron reduction potentials. For example, µ-tocopherol (µ-TOH)
slows lipid peroxidation by scavenging lipid peroxyl radicals.
Ascorbate is thus a supreme reducing system nutrient.
Reducing System Hazards and Clinical Trials:
There has been increasing interest in clinical trials of
reducing systems for prevention or treatment or preeclampsia.
The heterorganic function of reducing systems is exemplified by
two different reducing system bioassays used to study
preeclampsia. A substantial deficit in this serum reducing
system activity is observed in preeclampsia relative to normal
pregnancy because serum-transferrin iron binding reserve (apotransferrin)
is decreased. In contrast, reducing system activity measured as
the ability of plasma to scavenge water-soluble peroxyl radicals
is increased in preeclampsia and this is largely a function of
increased uric acid concentrations.
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