Download - SLAAPAPNEA AND OXIDATIVE STRESS
SLAAPAPNEA AND
OXIDATIVE STRESSJ. VERBRAECKEN
DEPT of PULMONARY MEDICINE AND SLEEP DISORDERS CENTER
UNIVERSITY HOSPITAL ANTWERP
Impact Outcome
Vascular system= Black Box
Structural and functional vascular changes
IHD
MI
Stroke
CV death
Hypertension
OSA
Confounders:AgeSexLipidsHypertensionSmokingDiabetesGenetics OXIDATIVE STRESS
?
1) What is oxidative stress?2) Is there oxidative stress in SAS ?3) Antioxidative capacity in SAS ?4) Links to vascular disease !?
SAS and oxidative stress
What is oxidative stress ? Definition
State of imbalance: Disturbance in the prooxidant-antioxidant balance in favour of the former.
Sies, 1985 Pro-Oxidants Antioxidants
What is oxidative stress ? Chemistry of oxidants/free radicals
Superoxide
Hydroxyl radical
Peroxy nitrite
Hydrogen peroxide
Spontaneous or dismutated by SOD
ROS=Reactive oxygen species
Oxidative injury to macromolecules
Reactive oxygen species (ROS)
Nucleic acid damage, mutation, carcinogenesis
Membrane damage Lipid peroxidation
Protein damage, enzymes, receptors, transporters
Polysaccharide damage, hyaluronic acid, arthritis
Detoxifying enzyme systems
LYTIC
NON-LYTIC
Sources of ROS in OSA
Normal oxygen transport– NADPH oxidase– Mitochondria (ETC, semi-
ubiquinon) Induction of enzyme
systems by hypoxia/reoxygenation– Xanthine Oxidase– Cyclooxygenase– Lipooxygenase– NO synthase– Haem oxygenase
Inflammatory leucocytes Cardiac tissues and vascular
cells Oxidation of small molecules:
– glucose – homocysteine
Hypoxia/reoxygenation Alterations in energy (ATP) metabolism
Lavie L et al, Sleep Med Rev 2003, 7(1):35-51Halliwell B Methods Enzymol 1990,186:1-85
Hypoxia/reoxygenation Hypoxia leads to alterations in gene expression
Activation of hypoxia-inducible factor 1 (HIF-1)Increased expression of hypoxia dependent genes
Forsythe JA et al, Mol Cell Biol 1996; 16:4604-4613. Huang L et al J Biol Chem 1996, 271:32253-9. Kallio P et al Proc Natl Acad Sci USA 1997:5667-72. Huang L et al, Proc Natl Acad Sci USA 1998, 95:7987-92
ROS
Activation transcription factors
NF-B, AP-1 HIF-1
VEGF Endothelin-1 EPO HSP Glycolytic enzymes Leptin/Leptin receptor iNOS apoptosisSystemic mediator release – proinflammatory cytokines
TNF, IL-1, …
Oxidative stress Defense mechanism: Antioxidative reserve
Antioxidant enzymes– Glutathion peroxidase (GPx)– Catalase– Superoxide dismutase (SOD)
Nonenzymatic antioxidants (radical scavengers): – Vit E– Vit A (Beta carotene)– Vit C (ascorbic acid)– Glutathion– Selenium– Albumin, ceruloplasmin,
bilirubine, uric acid, …
Action: works by keeping the delicate balance between the production of oxidants (ROS) and their catabolism by antioxidants.
Reoxygenation“Respiratory burst”: increased oxygen uptake
Coupling of GSH redox cycle to pentose phosphate pathway
NADPH
1) What is oxidative stress?2) Is there oxidative stress in SAS ?3) Antioxidative capacity in SAS ?4) Links to vascular disease !?
SAS and oxidative stress
Is there oxidative stress in SAS ? Superoxide release from polymorphonuclear neutrophils
Schulz R et al, AJRCCM 2000, 162:566-570
(after stimulation with the bacterial tripeptide fMLM and the calcium ionophor A23)
Is there oxidative stress in SAS ?8-Isoprostane in Breath condensate
Carpagnano G et al Chest 2002, 122:1162-1167
Marker oxidative stress Marker inflammation
Arachidonic acid + ROS isoprostanes
~AHI
~NC
Is there oxidative stress in SAS ? Total ROS production ± PMA by CD11+ and CD64+ cells
Granulocytes
Monocytes
Controls
OSADyugovskaya L et al, AJRCCM 2002, 165:934-939
x1.9 x5 x2.5 x2.7In OSA:
Basal ROS production
Basal ROS production ± PMA
1) What is oxidative stress?2) Is there oxidative stress in SAS ?3) Antioxidative capacity in SAS ?4) Links to vascular disease !?
SAS and oxidative stress
Antioxidative capacity in SAS
Wali S et al, Sleep 1998, 21(3):290-296
One night CPAP
No difference in GPx and Catalase
Antioxidative capacity in SAS
OSA Controls
N 17 8M/F 16/1 4/4Trolox Equivalent (TEAC) 2.210.6 1.970.52TEAC > 2 mmol/l 10 3TEAC < 1.5 mmol/l 1 1
Christou K et al, Sleep Med 2003, 4:225-228
TEAC ~ -AHI
Antioxidative capacity in OSA TEAC in OSA before/after CPAP
Changes in TEAC after CPAP therapy
Baseline After 1 month0
1
2
TEAC in CPAP groupTEAC in control group
p=0.08 (Paired T test)
Time
mM
Tro
lox
eq
Changes in TEAC after1 month CPAP therapy
TEAC before TEAC after0.75
1.00
1.25
1.50
1.75
Timem
M T
rolo
x Eq
De Backer L, AJRCCM 2003, 167(7):A174
Antioxidative capacity in OSASuperoxide dismutase (SOD) in OSA before/after CPAP
Changes in SOD during 1 month CPAP therapy
SOD before SOD after0
50
100
150
200
p<0.0001 (Paired T test)
Time
U/m
l
Changes in SOD before and after1 month CPAP therapy
Baseline After 1 month0
100
200
SOD in CPAP groupSOD in control group
p=0.0064(ANOVA)
NS(ANOVA)
Time
U/m
l
De Backer L, AJRCCM 2003, 167(7):A174
Antioxidative capacity in OSA Glutathion peroxidase (GPx) in OSA before/after CPAP
Changes in GPx after CPAP therapy
Baseline After 1 month0
5000
10000
15000
GPx in CPAP groupGPx in control group
p<0.001( Paired T test)
Time
U/L
Changes in GPx after1 month CPAP therapy
GPx before GPx after0
2500
5000
7500
10000
12500
15000
17500
p<0.001 (Paired T test)
Time
U/m
l
De Backer L, AJRCCM 2003, 167(7):A174
Changes in vit E after CPAP therapy
Baseline After 1 month0
10
20Vit E in CPAP groupVit E in control group
Time
µg/m
lAntioxidative capacity in OSA
Vit E in OSA before/after CPAP
CPAP: 14.5 to 15.4 g/mlCtrl: 14.2 to 13.8 g/ml
Antioxidative capacity in OSA Glutathion not affected by exposure to different O2-conditions
Norm O
Hyp O
H/N O
Norm V
Hyp V
H/N V
0.0
0.1
0.2
0.3
0.4
0.5
0.6p = 0,0087
Tota
l glu
that
ion
(nm
ol/m
ln c
ells
GSS
G e
quiv
alen
ts
Manuel-y-Keenoy et al Taormina 2006
Barcelo A et al Eur Respir J 2006, 27: 756-760
Antioxidative capacity in OSA
12 M CPAP
Grebe M et al AJRCCM 2006 173 897-901
1) What is oxidative stress?2) Is there oxidative stress in SAS ?3) Antioxidative capacity in SAS ?4) Links to vascular disease !?
SAS and oxidative stress
Links to CVD Abnormal and excessive lipid peroxidation
Basal level of lipid peroxidation (TBARs content)
Barcelo A et al, ERJ 2000, 16:644-647
Oxidation susceptibility of isolated LDL particles (lag phase)
Links to CVD Fatty acid peroxidation: exhaled pentane (and NO)
Olopade CO et al Chest 1997, 111:1500-04
Links to CVD Studies not supporting the oxidative stress hypothesis
Wali S et al, Sleep 1998, 21(3):290-296– Oxidative stress in vitro– Normal lipid peroxidation– Normal GPx– Normal catalase– CPAP: no influence
(one night)
Öztürk L et al, Clin Chim Acta 2003,332:83-88– Normal glutathion– Normal lipid peroxidation– Normal osmotic fragility of RBC– Limited number of patients
Svatikova et al, Eur Heart J 2005,26:2435-2439– Normal oxLDL– Normal lipid peroxidation– Normal plasma 8-isoprostane
Links to CVDPotential damage due to oxidant imbalance:
Expression of vascular adhesion molecules ICAM-1
» Ohga E et al, JAP 1999 VCAM-1, ICAM-1, E-selectine
» Chin K et al AMJ 2000 ICAM-A, IL-8, MCP-1
» Ohga E et al, JAP 2003 Proliferation of vascular smooth
muscle cells/proliferation of microvasculature (angiogenesis) VEGF: Gozal D Sleep 2002 VEGF: Schultz R AJRCCM 2002 VEGF: Imagawa S Blood 2001
Aggregation and activation of platelets, decreased fibrinolytic activity
– Sanner B et al, ERJ 2000– Arnulf I et al, JAMA 2002
Enhanced oxidation of LDL– Lipid peroxides - >>> foam cells
» Barcelo A et al, ERJ 2000 Break down of NO to peroxynitrate
NO+ O2- >>>>>>> OONO-
Induction of proinflammatory cytokines TNF, IL-6, IL-8
Increased expression of hypoxia dependent genes
OSA Hypoxia/Reoxygenation
NADH-oxidase xanthine oxidase mitochondrial dysfunction Homocysteine
ROS
Activation transcription factors HIF-1NF-B, AP-1VEGF Endothelin-1 EPO HSP Glycolytic enzymes
Systemic mediator release – proinflammatory cytokines
Monocyte neutrophil activation Lymphocyte activation Endothelial cell activation
Adhesion molecules expression
Monocyte lymphocyte/endothelial adhesion
Endothelial dysfunction
NO
Vascular disease
LDL peroxidation
Foam cells
O2-,H202
L. Lavie Sleep Med Rev 2003
SAS and oxidative stressConclusions
1) (O)SAS exerts an enhanced intravascular oxidative stress reaction
2) (O)SAS patients have an increased antıoxidative capacity (SOD, GPx)
3) CPAP can decrease oxidative stress4) CPAP can decrease oxidative capacity
(SOD, GPx)5) Oxidative stress is linked to CVD (with increased
adhesion to endothelial cells)