drug eluting stents – the cell biology andrew newby bristol heart institute ?
TRANSCRIPT
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Drug Eluting Stents – The Cell Biology
Andrew Newby BRISTOL HEART
INSTITUTE
?
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Basis of neointima formation
ONE WEEK
Thrombus
Inflammation
Injury
Stretch
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Early thrombus and later inflammation
% of specimens•Thrombus•Neutrophils•Macrophages•Giant cells
<3 d7279820
Histological findings in 55 coronary in-stent restenosis
specimens Farb et. al. Circulation 1999;95:44-52
4-11 d7883670
12-30 d24729710
>30 d008529
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More injury - more restenosis
Serial IVUS - Hoffman et. al. Am J Cardiol 1999;83:1170-4
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Smooth muscle cells and extracellular matrix
% of specimensSmooth muscle cellsProteoglycans and HA
<3 d0
4-11 d0
12-30 d45
>30 d100
Farb et. al. Circulation 1999;95:44-52
SMC are 59% of all cells25% of SMC PCNA, cyclinE, and cdk2 positive
Kearney et. al. Circulation 1997;95:1998-2002
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Where do neointimal cells come from?
Adventitial fibroblasts?
Medial SMC?
Circulating
stem cells?
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Importance of medial injury
Plaque Intact
media
Damaged
media
Intimal thickness (mm)
.2
.4
.6
.8
1
0
Farb et. al. Circulation 1999;95:44-52
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Growth factors promote neointima formation (Russell Ross)
m
SMC
SMC
SMC
PDGF
SMC
SMC
SMCSMC
SMC
bFGFIGF-1, TGF
Thrombin, 5HT
PDGF
m
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SMC in intact aorta don’t respond to growth factor –FCS induced thymidine incorporation
0.00E+00
2.00E+06
4.00E+06
6.00E+06
0 10 20 30 40 50 hours
DP
M/
g D
NA
isolated cells
aortic tissue
T Izzard et. al. Cardiovasc Res2002: 53; 242-52
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Control of smooth muscle cell cycle
G1
S
G2Mitosis
G0Growthfactors
SignalTrans-ductionMAPK
CyclinD/cdk4
DecreasedP16 and p27
ckis
CyclinE/cdk2
R
cdk
cyclinT
Y P
CK
I
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p27 levels are maintained and cdk4 kinase activity is inhibited in intact vessels
Intact
Isolated
Intact
Isolated
0 1 2 4 6 8 12 16 24 h0.5
p27 CKI
0 4 8 12 16 24 h
CyclinD/cdk4 activity T Izzard et. al. Cardiovasc Res2002: 53; 242-52
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Dual control of smooth muscle cell proliferation
G1
S
G2Mitosis
G0Growthfactors
SignalTrans-ductionMAPK
CyclinD/cdk4
DecreasedP16 and p27
ckis
CyclinE/cdk2
R
Cell Cycle
Matrix protein binding to cell surface integrins
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Basis of SMC migration
Matrix proteins
SignalTransduction
Pathways
Activationof CAM-kinase II
Engagementof cell
surfaceintegrins
Cytoskel-etal re-
arrangementChemo-attractant
Migration
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Matrix regulation of SMC
Contractile, quiescent SMC
BM, lamininType IV collagen
Fibronectin
Synthetic, migratingproliferating SMC
Fibronectin, osteopontin, vitronectin,Type I, IV, VIII collagen,Versican, hyaluronic acid
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Extracellular proteases combine with growth factors to promote neointima
m
SMC
SMC
SMC
MMPs
SMC
SMC
SMCSMC
SMC
MMPs, uPA, other proteases
Migrate
Divide
m
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‘Multiple key control’ of the cell cycle
G1
4,5PIP2 – 3,4,5 PIP3G0
PDGF
PI3K
Grb
SOS
raf
PKB mTOR
PLCI1,4,5P3DAG
PKC
ras MEK ERK1/2
PROTEIN KINASES
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Steps regulated by mammalian target of rapamycin
G1SMigration!PDGF
PI3K PKB
mTOR
p27 CKI
Matrix proteins
EIF-4EProtein synthesis
p70s6k
Gene expression
Marx and Marks, Circulation 2001;104:852-5. Sun, Circulation 2001;103:2967-72
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Inhibition of mTOR by sacrolimus (rapamycin) not tacrolimus
G1SMigration!
mTOR
p27 CKI
EIF-4EProtein synthesis
p70s6k
Gene expression
FKB
FKB
Sirolimus
Tacrolimus
Suzuki et al. Circulation 2001;104:1188-93
ChemokinesMCP-1, IL-6
CN
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Microtubules mediate migration and mitosis
Interphase Mitosis
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Paclitaxel disrupts the cytoskeleton and inhibits SMC migration and proliferation
Axel et al Circulation 1997; 96:636-45
actin
vimentin
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Conclusions –inhibition of SMC proliferation
G1
S
G2Mitosis
G0
Rapamycin -antiproliferative
SignalTrans-ductionMAPK
CyclinD/cdk4
DecreasedP16 and p27
ckis
CyclinE/cdk2
R
Cell Cycle
Matrix proteins
MMPI
Taxol –antimitotic
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Conclusions –inhibition of SMC migration
Rapamycin
Decreasedp27
cki
Matrix proteins
MMPI
SignalTransduction
Pathways
Activationof CAM-kinase II
Engagementof cell
surfaceintegrins
Chemo-attractant
Taxol
Cytoskel-etal rear-
rangement
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RapamycinThe jury considers the evidence