Role Oxidative Stress in Preeclampsia

wibowonoroyono@yahoo.com

WORLD MAP OF IRON

Low

Intermediate

High

WORLD MAP OF VITAMIN A

KEY :
Clinical Severe subclinical Moderate subclinical Mild subclinical VAD under control No data available

WORLD MAP OF ZINC

Widespread deficiency

Medium deficiency

Foliculogenesis Ovulation

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

Obstet Gynecol.2006; 108: 1145 52 Am J ClinNutr. 2007; 85: 231 7 AJOG. 2008; 118:210e1 e7

Spermatogenesis Motility Capacitation

Zinc:
Spermatogenesis initiation - maturation, enhance sperm motility (ATP system and phospolipid regulation) Involves in DNA-RNA Synthesis, promotes healthy growth of Seminiferous tubule Promotes healthy sperm and Seminiferous tubule development Spermatogonia differentiation and sprematid adhesion regulation; promote healthy reproductive organs development Prevents sperm cell membrane from lipid peroxidation; defends sperm from ROS-related events, mitochondria are promoted Protect sperm from oxidative stress

Vit B12: Vit B9: Vit A:

Vit E:

Vit C:

Calcium:

Initiates sperm motility

Assure the accurate formation of midpiece and flagella Change CNG cation channel function

Selenium: Nickel: DHA:

Concentrated in the sperm tail, for motility and capacitation

Precursor of putrescine, spermidine and spermine synthesis; Essentials for spermatogenesis and sperm motility Enhances sperm motility, maturation and spermatogenesis, supply energy to spermatozoa, protect cell membrane and DNA against ROS-induced damaged. ABB, 2011; 2; 182-97

Arginine: Leucine:

Prooxidant antioxidant Balance

ROS
Proliferation

Apoptosis

Necrosis

Cellular impact
News Physiol Sci 2004;19: 120-123

Vitamin A C E B D

Cu

Se

Zn

Fe

DHA

Cysteine

Folic

Ca

Es. Amino acid

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

-NO

ONOO-

Impaired physiological HOMEOSTATIS Impaired physiological Function function

Random cellular damage Specific signaling pathways

Decreased proliferative response detective host defenses

Normal growth and metabolism

Aging

Disease Cell death

Antioxidant defense in biological systems

System
Non-enzymic a-tocophero1 (vitamin E) b-carotene lycopene ubiquinol-10 ascorbate (vitamin C) glutathione (GSH) urate bilirubin flavonoids plasma proteins chemical Enzymic (direct) superoxide dismutases GSH peroxidases catalase Enzymatic (ancillary enzymes) conjug enzymes NADPH-quinone oxidoreductase GSSG reductase NADPH supply transport systems repair systems glutathione-S-transferases UDPglucuronosyl-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 CuZn enzyme, Mn enzyme, Fe enzyme see enzymes (GPx, PHGPx) ebselen as enzyme mimic heme protein, peroxisomes 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

Remarks

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

Insulin sensitivity: modulation by nutrients and inflammation

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. 118:29923002 (2008). doi:10.1172/JCI34260 http://www.progesteronetherapy.com/insulin-resistance.html , Journal of Endocrinology 2000; 166, 283291

Vitamin E -carotene Endoplasmic Reticulum NUCLEUS

DNA

Vitamins C and E -carotene GSH Glutathione Peroxidase Vitamin C Vitamin E

Catalase Cu/Zn SOD

Lysosomes Peroxisomes Cytoplasm Mitochondrion

Lipid Bilayer of All cellular membranes Vitamins C and E -carotene

Mn SOD+ Glutathione Peroxidase +GSH

FASEBJ 1: 441-445; 1987.

Electron transport system cytochromes P450 and b5 Xanthine oxidase hemoglobin Oxidative burst Myeloperoxidase enzyme system (phagocytes)

Endoplasmic Reticulum

NUCLEUS
DNA

Oxidases flavoproteins

Lysosomes Peroxisomes Cytoplasm Mitochondrion

Reduced flavins Transition metals

Lipid Bilayer of All cellular membranes

Lipoxygenases prostaglandin synthetase (NADPH oxidase (phagocytes)

Electron transport system Lipid peroxidation

FASEBJ 1: 441-445; 1987.

Tyrosine Kinases (src, P13K, JAK2, Pyk2, P13K, EGFR)

Transcription Factors (NF-B, HIF-1, AP-1) eNOS Uncoupling Ion Channels (Ca2+, K+ Channels) Matrix Metaloproteinases
Sachse, A. et al. J Am Soc Nephrol 2007;18:2439-2446

Tyrosine Phosphatases

ROS

Adhesion Molecules MAP Kinases (p38MAPL, JNK, ERK5)

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

CYTOKINES
eNOS iNOS NOS, COX XO, NAD(P)H COX-2

Pre-pro ET

NO ONOO-

O2

SOD

PGH2/TXA2 ET -1 PGI2/PGE2

H2O2 NO O2ONOOPGI2/PGE2 PGH2/TXA2

iNOS ET A

SMC
ET B

COX-2

Relaxation

Peripheral Resistance

Contraction

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

Endothelial signal transduction

Availability Of L-arginine
Aggregating platelets

eNOS expression

Availability of Cofactors for eNOS

Aggregating platelets
Cylokines Thrombin Hypoxia

EDRF/NO PGI2

Thrombin SHT SHT ADP TxA2 PDGF PDGF T T P Ach TK S AA

M

GI2 G0

SHT Ach

8 EDCF 8

BK
B

Ach
M

eNOS EDRF/NO

1234 +

AA A23187

PGI2

EDCFs

Endothelial Cells

EDHF EDRF/NO

Endothelin O2

O2 5 Oxided LDL Superoxide anion

PGI2
6 Intimal Thickening EDHF

PGH2 TxA2

Lapid-laden macrophage

K channel

cAMP

cGMP

+ +

Neutrophil

Contraction Proliferation
7

SMC response

Smooth Muscle Cells

Ang II
Gp91/ Nox1/ Nox4 p47 Cell Membrane

ROS
p22

c-Src PLD PLA2 PKC ROS

p67

p40 e

NAD(P)H O2
MMPs

NAD(P) + H O2
+/-

H2O2

ROS
+ + + Tyrosine Kinases +

+ MAPK JNK, p38MAPK ERK5, (ERK1/2)

Transcription Factors NFxB AP-1, HIF-1 Extracellular matrix proteins Pro-inflammatory gene expression

Ion channels

Tyrosine Phosphatases

Cell growth/apoptosis/survival

Contraction Dilation Migration

Vascular remodelling Vascular inflammation

Hypertensive Vascular Injury

Experimental Physiology 2005;90.4 pp 449-455

Adult Organism
Sympathetic nerve
Presynaptic 2receptor

Placenta

NE receptor
Gs AC

Plasma NE 2B receptor

Flt-1 sFlt-1

cAMP PKA Src Erk1/2 Nuclear

VEGF
VEGF mRNA

VEGF KDR

VEGF gene

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

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?

FIG. 8. Physiological role of ROS in insulin signaling cascades

Bashan, N. et al. Physiol. Rev. 89: 27-71 2009; doi:10.1152/physrev.00014.2008

Copyright 2009 American Physiological Society

FIG. 9. Cellular mechanisms for ROS-induced insulin resistance

Bashan, N. et al. Physiol. Rev. 89: 27-71 2009; doi:10.1152/physrev.00014.2008

Copyright 2009 American Physiological Society

Kidney
Tubolointerstitial Immune infiltration ROS
Intra renal ANG II

Systemic
NAD(P)H oxidase ROS Vascular remodelling NO inactivation Direct vasoconstriction

SNGFR Na reabsorption Pressure natriuresis

Na excretion

Volume Expansion HYPERTENSION

Vascular resistance

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

OXIDATIVE STRESS O2-, H2O2 NFB HSP Apoptosis

Neoantigen expression

Nonspecific inflammation

Autoimmune Reactivity??

INTERSTITIAL IMMUNE INFILTRATION

Mechanisms interrelating oxidative stress and interstitial infiltration of immune cells that have been demonstrated in experimental models of salt-sensitive hypertension.
Rodrguez-Iturbe B et al. Am J Physiol Renal Physiol 2004;286:F606-F616

2004 by American Physiological Society