5. dr. noroyono wibowo - role oxidative stress in preeclampsia

Role Oxidative Stress in Preeclampsia

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Low Intermediate High

WORLD MAP OF IRON

KEY : Clinical

Severe subclinical

Moderate subclinical

Mild subclinical

VAD under control

No data available

WORLD MAP OF VITAMIN A

Widespread deficiency Medium deficiency

WORLD MAP OF ZINC

Foliculogenesis – Ovulation

Obstet Gynecol.2006; 108: 1145 – 52 Am J ClinNutr. 2007; 85: 231 – 7

AJOG. 2008; 118:210e1 – e7

Fe, Zn, Protein, Vit. A, C, D; Protein; Antioxidant, DHA

• Zinc:

• Spermatogenesis initiation - maturation, enhance sperm motility (ATP system and phospolipid regulation)

• Vit B12:

• Involves in DNA-RNA Synthesis, promotes healthy growth of Seminiferous tubule

• Vit B9:

• Promotes healthy sperm and Seminiferous tubule development

• Vit A:

• Spermatogonia differentiation and sprematid adhesion regulation; promote healthy reproductive organs development

• Vit E:

• Prevents sperm cell membrane from lipid peroxidation; defends sperm from ROS-related events, mitochondria are promoted

• Vit C:

• Protect sperm from oxidative stress

• Calcium:

• Initiates sperm motility

• Selenium:

• Assure the accurate formation of midpiece and flagella

• Nickel:

• Change CNG cation channel function

• DHA:

• Concentrated in the sperm tail, for motility and capacitation

• Arginine:

• Precursor of putrescine, spermidine and spermine synthesis; Essentials for spermatogenesis and sperm motility

• Leucine:

• Enhances sperm motility, maturation and spermatogenesis, supply energy to spermatozoa, protect cell membrane and DNA against ROS-induced damaged.

Spermatogenesis – Motility – Capacitation

ABB, 2011; 2; 182-97

Prooxidant – antioxidant Balance

Cellular impact

RO

S

Proliferation Apoptosis Necrosis

News Physiol Sci 2004;19: 120-123

Vitamin Cu Se Zn Fe DHA Cysteine Folic Ca Es. Amino acid

A C E B D

Endogenous Sources Mitochondria Peroxisomes Lipoxygenases NADPH oxidase Cytochrome P450

Antioxidant defense Enzymatic systems: CAT, SOD, GPx, Prdx,Non-enzymatic systems: Glutathione Vitamins (A, C and E)

Exogenous Sources UV light Ionizing Radiation motherapeutics Inflammatory Cytokines Environmental toxins

-OH OH2

- ROS H2O2

-NO2

-RO

ONOO-

-NO

Impaired physiological ← HOMEOSTATIS→ Impaired physiological Function function

Decreased proliferative response detective host defenses

Normal growth and metabolism

Random cellular damage

Specific signaling pathways

Aging Disease Cell death

System Remarks

Non-enzymic

a-tocophero1 (vitamin E)

b-carotene

lycopene

ubiquinol-10

ascorbate (vitamin C)

glutathione (GSH)

urate

bilirubin

flavonoids

plasma proteins

chemical

radical chain-breaking

singlet oxygen quencrher

singlet oxygen quencher

radical scavenger

diverse antioxidant functions

diverse antioxidant functions

radical scavenger

plasma antioxidant

plant antioxidants

metal binding, e.g. coeruloplasmin

food additives, drugs

Enzymic (direct)

superoxide dismutases

GSH peroxidases

catalase

CuZn enzyme, Mn enzyme, Fe enzyme

see enzymes (GPx, PHGPx) ebselen as

enzyme mimic

heme protein, peroxisomes

Enzymatic

(ancillary enzymes) conjug enzymes

NADPH-quinone oxidoreductase

GSSG reductase

NADPH supply

transport systems

repair systems

glutathione-S-transferases’ UDP-

glucuronosyl-transferases

two-electron reduction

maintaining GSH levels

NADPH for GSSG reductase

GSSG export, thioether (S-conjugate)

DNA repair systems

oxidized protein tumover

oxidized phospholipid turnover

Antioxidant defense in biological systems

Postbinding defect in insulin action during pregnancy is probably related to increasing amounts of progesterone,

cortisol, PRL, and placental lactogen.

Progesterone is implicated in insulin resistance during pregnancy by inhibiting the PI3-kinase pathway at the step of (I) IRS1 expression and (II) distal to Akt, and by (III) suppressing the PI3-kinase independent pathway of TC10 activation by affecting Cbl phosphorylation.

JCEM 1988;67;2: 341-347 Am J Physiol Endocrinol Metab (January 13, 2010). doi:10.1152/ajpendo.00649.2009

Amino Acid Arginine, Carnitine Cysteine, Glutamine Glycine, Isoleucine Leucine, Taurine Valine

Mineral Chromium Selenium Zinc Ca

Vitamins B1, B2, B3 B5, B6, B12 Biotin, Choline Folic acid, Inositol Ascorbic acid

Lipoic acid Co Q10 D-Ribose Milk thistle (81.79% silymarins

J. Clin. Invest. 118:2992–3002 (2008). doi:10.1172/JCI34260 http://www.progesteronetherapy.com/insulin-resistance.html , Journal of Endocrinology 2000; 166, 283–291

Insulin sensitivity: modulation by nutrients and inflammation

http://www.progesteronetherapy.com/insulin-resistance.html



FASEBJ 1: 441-445; 1987.

Vitamin E

-carotene

NUCLEUS Endoplasmic Reticulum Vitamins C and E

-carotene

Lysosomes Peroxisomes Cytoplasm

Mitochondrion

GSH

Vitamin C

Vitamin E

Glutathione Peroxidase

Catalase

Cu/Zn SOD

Lipid Bilayer of All cellular membranes

Vitamins C and E -carotene

Mn SOD+ Glutathione Peroxidase +GSH

DNA

FASEBJ 1: 441-445; 1987.

Electron transport system cytochromes P450 and b5

Xanthine oxidase hemoglobin

NUCLEUS Endoplasmic Reticulum

Oxidative burst Myeloperoxidase enzyme system

(phagocytes)

Lysosomes Peroxisomes Cytoplasm

Mitochondrion Reduced flavins

Transition metals

Electron transport system

Oxidases flavoproteins

Lipid Bilayer of All cellular membranes

Lipoxygenases prostaglandin

synthetase (NADPH oxidase (phagocytes)

Lipid peroxidation

DNA

Sachse, A. et al. J Am Soc Nephrol 2007;18:2439-2446

Tyrosine Kinases (src, P13K, JAK2,

Pyk2, P13K, EGFR)

Tyrosine Phosphatases

Adhesion Molecules

MAP Kinases (p38MAPL, JNK, ERK5)

Matrix Metaloproteinases

Transcription Factors (NF-B, HIF-1, AP-1)

eNOS Uncoupling

Ion Channels (Ca2+, K+ Channels)

ROS

Role of ROS derived from NADPH oxidase in VEGF signaling linked to angiogenesis.

Ushio-Fukai M Cardiovasc Res 2006;71:226-235

Copyright © 2006, European Society of Cardiology

Vila, E. et al. Am J Physiol Heart Circ Physiol 288: H1016-H1021 2005; doi:10.1152/ajpheart.00779.2004

CYTOKINES

eNOS iNOS COX-2

SOD

iNOS COX-2

NOS, COX XO, NAD(P)H

Pre-pro ET

ET -1 PGH2/TXA2

PGI2/PGE2

NO

O2

H2O2

ONOO-

O2-

PGI2/PGE2 PGH2/TXA2

Relaxation

ONOO-

NO

Peripheral Resistance

Contraction

ET A ET B

SMC

- +

K channel cAMP cGMP

Contraction Proliferation

SMC response

- +

Smooth Muscle Cells

↓ EDHF

↓EDRF/NO

↓ PGI2

Intimal Thickening

6

7

Neutrophil

Endothelial signal transduction

1 Availability

Of L-arginine

2 eNOS expression

3 Availability of Cofactors for eNOS

4

Aggregating platelets

SHT

EDCFs

Ach AA

A23187

Cylokines Thrombin Hypoxia

EDCF

SHT TxA2

PDGF

Aggregating platelets

Thrombin ADP SHT

PDGF Ach

EDRF/NO PGI2

EDHF

B M

BK

Ach

AA

PGI2 EDRF/NO

eNOS

↓GI2 ↓G0 M

TK S

T T P

↑Endothelin

+

+

-

Superoxide anion

5 ↓O2 ↓ Oxided

LDL

Lapid-laden macrophage

1 2 3 4

8

8

↑ O2

PGH2 TxA2

?

Endothelial Cells

S M

Experimental Physiology 2005;90.4 pp 449-455

Cell Membrane p22

Gp91/ Nox1/ Nox4

p67 p40 p47

ROS

ROS

Ang II

•c-Src •PLD •PLA2

•PKC •ROS

MMPs

Transcription Factors

NFxB AP-1, HIF-1

Tyrosine Kinases

Tyrosine Phosphatases

MAPK JNK, p38MAPK ERK5, (ERK1/2)

Ion channels

•Vascular remodelling •Vascular inflammation

Hypertensive Vascular Injury

Pro-inflammatory gene expression

Extracellular matrix proteins

Cell growth/apoptosis/survival

•Contraction •Dilation •Migration

O2 •O2ˉ H2O2

NAD(P)H NAD(P) + H

+ +

+

+ +

eˉ

-

+/-

Hattori, Y. et al. Circ Res 2007;101:642-644

Adult Organism Placenta Sympathetic nerve

Presynaptic 2receptor

NE receptor

Gs

AC

cAMP

PKA

Src

Erk1/2

Nuclear VEGF mRNA

VEGF

VEGF gene

Plasma NE 2B receptor

-

Flt-1

sFlt-1

VEGF

KDR

Angiogenesis

Antioxidant therapy: Clinical results are controversial. Ideal antioxidant - Must get antioxidant to correct site (ADME). - Must prevent damage to correct macromolecule. - Must be stable after scavenging radicals. - No side effects. Problem - May downregulate endogenous antioxidant defense system. - May disrupt cooperative action of antioxidant defense system. Elevation of antioxidant defense system including antioxidant enzymes?

Rodríguez-Iturbe B et al. Am J Physiol Renal Physiol 2004;286:F606-F616

Intrarenal ANG II activity resulting, at least in part, from ANG II-positive interstitial mononuclear cells and tubular cells induces

sodium retention by the combined effects of reducing filtered sodium, increasing proximal tubular sodium reabsorption, and

impairing pressure-natriuresis. Increased intrarenal ANG II in association with oxidative stress constitutes a feedback loop for the

maintenance of interstitial renal inflammation.

Kidney Systemic

Tubolointerstitial Immune infiltration

↑ Intra renal ANG II

↓ Na excretion

Volume Expansion

↓ SNGFR ↑ Na reabsorption

↓ Pressure natriuresis

↑ NAD(P)H oxidase

ROS ROS

NO inactivation Direct vasoconstriction

Vascular remodelling

↑ Vascular resistance

?

HYPERTENSION

Rodríguez-Iturbe B et al. Am J Physiol Renal Physiol 2004;286:F606-F616

©2004 by American Physiological Society

Mechanisms interrelating oxidative stress and interstitial infiltration of immune cells that have been

demonstrated in experimental models of salt-sensitive hypertension.

OXIDATIVE STRESS

O2-, H2O2 NFB HSP Apoptosis

Nonspecific

inflammation

Autoimmune

Reactivity??

Neoantigen

expression

INTERSTITIAL

IMMUNE INFILTRATION

5. dr. noroyono wibowo - role oxidative stress in preeclampsia

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