bichat pathofys asc ao aneur esc 2011

8/2/2019 Bichat Pathofys Asc Ao Aneur Esc 2011

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DECLARATION OF CONFLICT OF INTEREST


2/15

Pathophysiology of aneurysms of thethoracic ascending aorta

Unit 698, vascular remodelling

X. Bichat 75018 Paris


3/15

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


4/15

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


5/15

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


6/15

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


7/15

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


9/15

Elastic fibres FibronectinFibronectin

LTBP-1TGF-1 MergeMerge

P-SMAD 2

TGF-b mobilization and SMAD2 dissociation

LTBP-1

Gomez D & al. J. Pathol. 2009


10/15

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


11/15

Anti-protease: Protease Nexin-1 (anti-plasmin, anti-tPA)

Controls

TAAs


12/15

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


13/15

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

bichat pathofys asc ao aneur esc 2011

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