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DECLARATION OF CONFLICT OF INTEREST
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Pathophysiology of aneurysms of thethoracic ascending aorta
Unit 698, vascular remodelling
X. Bichat 75018 Paris
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A: Control B: TAA
Frequency (%)
0
5
10
15
20
25
30
10 90
Age (year)
Marfan syndrome
Bicuspidy
Degenerative
38.3
+/- 1.854.6
+/- 2.2
67.5
+/- 1.2
Touat Z. & al. ATVB 2007
Etiologic Diversity & Clinical dimorphism
monogenic degenerativebicuspid valves
anvrysmes dissections
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elastolysis
Pathological monomorphism common to aneurysms & dissections:
mucoid degeneration = SMC disappearance, MMP retention
BAVmucoid degeneration
SMC actin
Borges LF & al. Human Pathol. 2007
Matrilysin
Borges LF & al. Human Pathol. 2009
SMC disappearance
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100
rPg rPn
90
80
150
200
250
300
350
400
450
500
550 *
TAAControl
TAAPlasmin/anti-plasmin(ng/mg)
Control0
10
20
30 *
Control TAAPlasminogen/Plasmin(a.u.)
Proteases: Plasmin activation
controls TAA
plasmin
t-PA
*
t-PA (protein)
10
20
30
0
40
arbitraryunits(OD)
Control TAA
Borges LF & al. HistoPathol. 2010
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ControlTAAr t-PA160
10090
70
t-PA mRNA
control TAA
-,5
0
,5
1
1,5
2
2,5
3
3,5
4
4,5
Control TAA
Proteases: Plasminogen activator: t-PA
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LMW-
uPA
33.5 kDa
TAAControl
Casein zymography
0
Arbitraryunits
LMW-UPA (OD)
Control
*
TAA
C
u-PA mRNA
contro
l
TAA-,5
0
,5
1
1,5
2
2,5
3
3,5
4
4,5
Proteases: Plasminogen activator: u-PA
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Elastic fibresFibronectin
FibronectinFibronectin
30
40
50
60
70
80
90
100
110
120
130140
Control TAA
*
Fibronectin(a;u;)
250
150
100
75
50
NScontrol TAA
FN protein
Compensatory responses: fibronectin/fibrillin turn-over
0
,5
1
1,5
2
2,5
3
Control
FN mRNA**
TAA
Fibrillin
control
TAA
Fibrillin
Borges LF & al. HistoPathol. 2010
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Elastic fibres FibronectinFibronectin
LTBP-1TGF-1 MergeMerge
P-SMAD 2
TGF-b mobilization and SMAD2 dissociation
LTBP-1
Gomez D & al. J. Pathol. 2009
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1a 1b
CONTROL
TAA
1a 1b
SMAD2 PROMOTER
EPIGENETIC REGULATIONON SMAD2 PROMOTER
INCREASE IN1a PROMOTER ACTIVITY
SMAD2 PROMOTER
SMAD2 PROMOTER
mRNA
mRNA
SPECIFICITY:SMC-SPECIFIC
1a TSS SPECIFIC
Compensatory response: epigenetic modulation in aneurysms
INCREASE INH3K9/14ac AND H3K4me
Gomez D & al. CardioVasc. Res. 2011
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Anti-protease: Protease Nexin-1 (anti-plasmin, anti-tPA)
Controls
TAAs
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PAI-1
Control TAA
GAPDH
Control TAA
*
P
N-1protein(a.u.)
10
20
30
0
PAI-1mRNA
level
,1
,2
,3
,4
,5
Control
*
PN-1mRNA
level
0
,5
1
1,5
2
2,5
3 *
Control TAA TAA
*
PAI-1ng/gtissue
0
10
20
30
40
50
60
Control TAA
Anti-protease: PN-1 and PAI-1 expression
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Control TAA
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
-1200 -1000 -800 -600 -400 -200 0 200
Smad2Binding
PN-1 promoter0
,2
,4
,6
,8
1
Smad2binding * *
-1000 -600
Control TAA
Smad2bind
ing
*
0
,2
,4
,6
,8
1 *
-1000 -600
PAI-1 promoter-1200
Smad2
binding
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
-1000 -800 -600 -400 -200 0 200
Epigenetic mechanism
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0
,5
1
1,5
2
2,5
3
3,5
Smad2 mRNA
Control TAA Dissection-,5
0
,5
1
1,5
2
2,5
3
Fibronectin
Control TAA Dissection0
,05
,1
,15
,2
,25
,3
,35
,4
,45
PN-1 mRNA
Control TAA Dissection
-1
0
1
2
3
4
5
6
u-PA mRNA
Control TAA Dissection-,5
0
,5
1
1,5
2
2,5
3
3,5
4
Control TAA
Dissection
t-PA mRNA
Clinical relevance: Plasmin activation is common to progressive dilation andacute rupture, but, epigenetic resistance is restricted to progressive dilation.
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molecules
SMC apoptosiscells
tissue
Matrix degradation
clinics anvrysmes dissections
fibrillin/TGFbR/myosin/Acta 2/notch-1/Glut 10
Proteases
Etiologic Diversity & Phenotypic Monomorphism
monogenic degenerativebicuspid valves
mucoid degeneration
Epigenetic resistance No epigenetic resistance