Oxidative Stress in Preeclampsia

 Preeclampsia – Introduction & prevalance
 Risk factors, symptoms & pathophysiology
 Free radicals, ROS & RNS
 Oxidative stress in Preeclampsia
 Oxidative stress markers
 Antioxidants
30-Oct-17Rajeev Gandham 2

 Preeclampsia is progressive disorder leads to maternal &
perinatal morbidity and mortality.
 The term, preeclampsia, a condition prior to eclampsia (Greek
word “eklampsis” meaning sudden flashing) is a systemic
syndrome.
 Pregnancy Induced Hypertension, characterized by New onset
of hypertension (140/90 mmHg) & proteinuria (≥300 mg/24 h)
after 20 weeks of gestation in previously normotensive non-
proteinuric pregnant women.
30-Oct-17 3Rajeev Gandham

 In low and middle income countries, about 10% of all
maternal deaths.
 Approximately, 800 women die from pregnancy and child
birth related complications around the world every day
 An estimated >60,000 maternal deaths worldwide per year.
 Preeclampsia and eclampsia accounts for 24% of all maternal
deaths in India.

› Genetic risk factors
› Family history of preeclampsia
› First pregnancy
› Previous pregnancy with preeclampsia
› Gestational age < 20 & > 40 years
› Women who are carrying twins, triplets or more
› Prolonged interval between pregnancies
› Women with gestational diabetes
› A hydatidiform mole
Continued…

› Conception by in-vitro fertilization (IVF)
› Nulliparity
› Pre-existing - Diabetes Mellitus, Metabolic syndrome, Insulin
resistance, Uncontrolled Hyperthyroidism, PCOS & Chronic
hypertension
› Thrombophilia
› Systemic lupus erythematosus or antiphospholipid syndrome
› Kidney disease
› Periodontal disease during pregnancy
› Environmental factors such as living at high altitude & stress

 From mild to severe due to slow or rapid progress of
disease condition.
 They include –
› Persistent headache
› Blurred vision
› Right upper quadrant pain
› Pulmonary edema
› Vomiting and abdominal pain
› Acute renal failure (ARF)
Continued…

› Acute hepatic failure
› Bleeding at the time of delivery & postpartum bleeding
› Maternal mortality & morbidity
 Complications:
› Premature delivery
› Intrauterine growth restriction
› Perinatal mortality and morbidity
› HELLP syndrome
› Seizures

 Predominantly as consequence of abnormal placentation.
 Disease process can involve multiple organ systems &
› Involvement of utero-placental blood flow
› Vascular resistance
› Endothelial integrity & endothelial damage
› Coagulation system
 It can occur in early pregnancy termed as “early onset
preeclampsia” at <34 weeks of gestation and “late onset
preeclampsia” after 34 weeks of gestation.

 Definition:
 Free radical is a molecule or molecular fragment that contains
one or more unpaired electrons in its outer orbital.
 Represented by a superscript dot, (R•).
 Oxidation reactions ensure that molecular oxygen is
completely reduced to water.
 The products of partial reduction of oxygen are highly
reactive, called Reactive Oxygen Species or ROS

 Superoxide anion radical (O2
-•)
 Hydroperoxyl radical (HOO•)
 Hydroxyl radical (OH•)
 Lipid peroxide radical (ROO•)
 Nitric oxide (NO•)
 Alkoxyl L(R)O•

 Peroxynitrite (ONOO-)
 Hypochlorite (-OCl)
 Hydroperoxide L(R)OO•)
 Hydrogen peroxide (H2O2)
 Singlet oxygen (1O2)

 Independent existence
 Contains an unpaired electrons
 Extreme reactivity
 Short life span
 Generation of new ROS by chain reaction
 Damage to biomolecules, cells & various tissues

 An imbalance between ROS production & breakdown by
endogenous antioxidants defense.
 May lead to tissue injury.
 OS may result in damage to macromolecules
› Carbohydrates
› Lipids
› Proteins
› Nucleic acids

 Oxygen containing molecules that have a higher reactivity
than the ground state oxygen.
 High doses and/or inadequate removal of ROS results in
oxidative stress, which may cause damage to biological
macromolecules.
 There are many different sources by which the ROS are
generated.

 Exogenous sources include
› Exposure to cigarette smoke
› Emission from automobiles & industries
› Excess alcohol
› Asbestos
› Exposure to ionizing radiation
› Bacterial, fungal or viral infections
 Endogenous sources of ROS includes as
 By-products of normal & essential metabolic reactions such as
energy generation from mitochondria or the detoxification
reactions involving the liver cytochrome P-450 system.

 NADPH Oxidase
 Xanthine Oxidase
 Nitric oxide synthase (NOS)
 Lipoxygenases
 Cyclo-oxygenases
 Cytochrome P450 enzyme
 Mitochondria

 Sources of superoxide in neutrophils & vascular endothelial
cells, also from neutrophil respiratory burst.
 Increased feto-placental vascular shear stress & enhanced
angiotensin II sensitivity, stimulates NADPH oxidase activity
 NADPH oxidase, increased in early-onset Preeclampsia
 NADPH oxidase mediates superoxide generation.

 In Preeclampsia, improper spiral arteries implantation leads to
hypoxicated tropoblastic tissue destruction, produces
hypoxanthine & xanthine, cytokines leads to inflammation.
 Hypoxia stimulates Xanthine oxidase activity.
 Hypoxanthine , Xanthine is converted to UA & H2O2 by XO
 XO & UA levels increased in Preeclampsia
 XO, expressed in cytotrophoblast, syncytiotrophoblast &
villous stromal cells.
 XO, mediates superoxide radical generation.

 NO• is vasodilator
 Half-life: 1-30s
 Mediates endothelial function by regulating
› Vascular tone, Platelet aggregation, Leukocyte adhesion,
Smooth muscle cell development
 Types of NOS:
 Neuronal – nitric oxide synthase (nNOS)
 Inducible – nitric oxide synthase (iNOS)
 Endothelial – nitric oxide synthase (eNOS)
 eNOS associated with trophoblast differentiation.

 eNOS, a source of superoxide formation & ↓NO production
 ↓Tetrahydrobiopterin (BH4), cofactor of eNOS & post-
translational changes regulate eNOS function.
 TNF-α & CRP ↑ in Preeclampsia
 TNF-α downregulates eNOS & mitochondrial dysfunction
(MD) and elevates ROS production
 BH4, eNOS & NO• still not well understood in Preeclampsia.

 Superoxide radical (O2
-•) used by immune system to kill
invading pathogens
 Main quencher of superoxide radical (O2
-•) is SOD,
converts it to H2O2 & water.
 H2O2 is neutralized by catalase.

 Peroxynitrite (ONOO-), primary product of the reaction of
superoxide & nitric oxide.
 It is a new member of the nitroxidative array of reactive
metabolites.
 Half-life: 10-20 ms
 ONOO- reacts with protein tyrosine residues to produce 3-
nitrotyrosine (3-NT)

 ONOO- can also cause DNA damage & lipid structural
alteration
 Mechanism of nitration:
 Peroxynitrite & heme-peroxidase pathways, lead to
concomitant formation of tyrosyl radicals & •NO2 , which
combine at diffusion-controlled rates to form 3-nitrotyrosine.
 Nitroxidative stress in Preeclampsia:
 3-NT levels in Preeclampsia are controversial.
 MAPK significantly nitrated in Preeclampsia
 MAPK involved in connective tissue remodeling.

 Placental trophoblasts and endothelial cells constitute the
placental barrier which effectively separates the fetal and
maternal circulation.
 Elevated oxidative stress causes tissue damage and
inflammation which alters the barrier and causes leakage of
fetal and placental derived factors in to the maternal
circulation

 Thus oxidative stress disturbs the normal redox state of the
cell and brings toxic effects on the cellular components which
results in apoptosis.
 Due to high reactive nature of reactive species and its
influence on endoplasmic reticulum triggers unfolded protein
response pathway in placental cell.
 This results in accumulation of abnormally folded proteins
with high turnover accounts to cell death and the basis of
pathogenesis of preeclampsia

 The effect of oxidative stress at systemic level occurs by
inflammation process, which is mediated through the
localization of leukocytes, pro-inflammatory cytokines,
adhesion molecules, chemokines.
 ↑ superoxide production in oxidative stress binds NO & limits
its availability which results in an altered endothelial function
and also inflammatory process.
 This elevated systemic oxidative stress responsible for the
release of substances from placenta into maternal circulation
in preeclampsia

 Preeclampsia is characterized by inflammatory response after
hypoxia / reperfusion insult.
 In Preeclampsia, placental reperfusion injury converges into a
damaging inflammatory response, responsible for
inflammation & oxidative damage orchestrated by OS
 Immediately after placental reperfusion injury, reestablished
blood flow releases cytokines & inflammatory factors like
TNF-α, IL-6, IL-10 & CRP and damaging levels of ROS like
superoxide, in response to these events.

 Increased ROS may eventually trigger a redox signaling
process to induce cell apoptosis.
 Evidences suggest that reduced perfusion due to aberrant
placentation & swallow trophoblast invasion, triggers
placental oxidative stress, leading to intravascular
inflammatory response and endothelial dysfunction, leading
to elevated blood pressure.
 These situations are probably involved in the pathogenesis of
preeclampsia.

 Lipid peroxidation (MDA)
 F2 – isoprostanes (8 – epi-prostaglandin F2α)
 Nitrotyrosine
 Protein carbonyls
 Advanced oxidation protein products (AOPP)
 DNA damage – 8-hydroxy – 2-deoxyguanosine
 MDA/total antioxidant capacity ratio etc, increased in
Preeclampsia

 Oxidative stress index (OSI)
 Total antioxidant status (TAS)

 Definition:
 Substance (present in low concentrations compared to an
oxidizable substrate) that significantly delays or inhibits
oxidation of a substrate.
 Antioxidants may be considered as the scavengers of free
radicals.
 Enzymatic antioxidants:
 Superoxide dismutase
 Catalase

 Paraoxonase
 Glutathione peroxidase
 Glutathione Reductase
 Glutathione –s-transferase
 Glucose -6-phosphate dehydrogenase
 Thioredoxin reductase

 Non enzymatic
1. Nutrient antioxidants:
 Carotenoids
 Vitamin E & C
 Selenium
2. Metabolic antioxidants:
 Glutathione
 Uric acid
 Bilirubin

 Ceruloplasmin
 Ubiquinones
 Ferritin
 Transferrin
 Albumin
 Thioredoxin

 Isoforms of SOD:
1. Copper-zinc-SOD: Cytosol
2. Mn-SOD: Mitochondria
3. Extracellular SOD: Vascular cell
 Normal conditions, •O2
- is low & SOD is high, catalyses
dismutation of •O2
- as H2O2 & O2
 Catalase:
 Catalase converts H2O2 to H2O and O2

 SOD-1 & GPx-1/3/4 deficiencies are key antioxidants in
pathogenesis of Preeclampsia.
 ↓SOD-1 level will cause an increase in superoxide anion,
which then reacts with NO to form peroxinitrite.
 This reduce the bioavailability of NO
 Glutathione peroxidase (GPx) deficiency second key player in
etiology of Preeclampsia
 ↓activity of GPx associated with synthesis of vasoconstrictive
eicosanoids, e.g., F2-isoprostanes & thromboxanes (↑ in PE)

 It detoxifies H2O2 to H2O, while reduced glutathione (G-SH)
is converted to oxidized glutathione (GS-SG).
 Contains selenium.
 The reduced glutathione can be regenerated by the enzyme
glutathione reductase utilizing NADPH .
 The HMP hunt is the major source of NADPH.

 Catalyzes the conjugation of the reduced form
of glutathione (GSH) to xenobiotic substrates (detoxification)
 The GST family consists of three superfamilies:
cytosolic, mitochondrial and microsomal.

Oxidative Stress in Preeclampsia

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Oxidative Stress in Preeclampsia