|
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 the present is most popular
the theory of oxidative stress, that lead 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. This chapter
reviews these oxidative stress and the current status of
reducing systems like Vit. C and E in pre-eclampsia.
OXIDANT-ANTIOXIDANT INTERACTIONS:
Free Radicals And Reactive Oxygen Species:
A free radical is any molecular species capable of independent,
albeit brief, existence that contains one or more unpaired
electrons.
There are comprehensive reviews on interactions between reactive
oxygen species and reducing systems in human health and disease.
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.
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. The levels of
these proteins were increased approximately 2- to 3-fold in the
pre-eclamptic placentae compared to the normal placentae. These
results indicated that the pre-eclamptic placentae were exposed
to oxidative stress and that the protein thiol/disulphide
oxidoreductases were adaptively induced in pre-eclamptic
placentae, suggesting possible roles for thioredoxin,
glutaredoxin, and protein disulphide isomerase in protecting
placental functions against oxidative stress caused by pre-eclampsia.
A diverse array of cellular and extra cellular fluid reducing
systems has evolved to control and compartmentalize, but not
necessarily eliminate, the production of reactive oxygen
species; Reducing systems examined in normal and pre-eclamptic
pregnancies include the enzymatic reducing systems (super oxide
dismutases (SOD), catalase, and glutathione peroxidase), and
transition metal binding proteins (transferrin, ceruloplasmin,
and ferritin).
Lipid Peroxidation:
Lipid peroxidation has received a great deal of attention in preeclampsia.
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:
Circulating lipids have diverse effects upon endothelial cell
function, and dyslipidemia is associated with endothelial cell
dysfunction. Continued oxidation is facilitated (primed) by “
feed-forward” interaction of lipid hydroperoxides in the LDL
particle with cell-derived oxidants. 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:
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.
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. 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:
The dyslipidemia of preeclampsia is best understood in the
context of lipid changes during normal pregnancy.
Lipid Metabolism In Normal Pregnancy:
Circulating lipids are carried primarily in lipoproteins, which
are composed primarily of free and esterified lipids, proteins (apolipoprotein),
and phospholipids. The two main cholesterol- carrying
lipoproteins are LDL and high-density lipoproteins (HDL). The
triglyceride-enrichment of LDL and HDL contributing to hyper-
triglyceridemia may be due to increased cholesteryl ester
transfer protein (CETP) activity during normal pregnancy.
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
12,14,101 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:
For example, µ-tocopherol (µ-TOH) slows lipid peroxidation by
scavenging lipid peroxyl radicals (LOO·). Ascorbate is thus a
supreme reducing system nutrient. 133
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-transferring 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. Xanthine oxidase produces
uric acid (an reducing system) but can also be a major source of
local reactive oxygen species, such as hydroxyl radicals (OH),
can generate uric acid radicals that are themselves capable of
causing cell damage. It would not be surprising if the effects
of a xanthine-oxidase inhibitor, such as allopurinol, were
complex in preeclampsia.
In one trial vitamin E supplementation failed to have a salutary
effect on the course of already established preeclampsia, but as
noted, plasma vitamin E deficiency is not a characteristic of
the disorder. In another report, a randomized control trial in
which a combination of reducing systems were given orally for
1-2 weeks) to women with established early-onset preeclampsia
(usually severe), no changes in maternal placental
thiobarbituric acid- reactive substances (an index of lipid
peroxidation) and no alterations in glutathione concentration
were noted. There was, however, a tendency for the treated group
to deliver later. Also, decreased concentration of uric acid and
increased concentrations of vitamin E, but no differences in
thiobarbituric acid-reactive substance, were noted in the sera
of these treated subjects.
In essence, although the potential for administering reducing
systems to prevent or treat preeclampsia is appealing, we
suggest that their incorporation into clinical care be deferred
until (1) appropriate reducing systems can be established and
(2) clinical trials demonstrate safety and efficacy for both
mother and baby.
EXERCISE: AN EFFECTIVE REDUCING SYSTEM FOR PREVENTION OF PRE-ECLAMPSIA?
It is reported that regular exercise increases beneficial
reducing systems in pregnant women, which in turn reduces
oxidative stress.
|
