Konstantinos Stellos, MD Goethe University Frankfurt

Konstantinos Stellos, MD Goethe University Frankfurt

Konstantinos Stellos, M.D.
Vascular Inflammation Group-Leader
Institute of Cardiovascular Regeneration, Centre of Molecular Medicine &
Department of Cardiology, Centre of Internal Medicine III
Goethe University Frankfurt
Platelets in Vascular Homeostasis
Stellos K, Curr Vasc Pharmacol, 2012 In Press
miRNAs: powerful new regulators of vascular biology and
provocative therapeutic targets
Van Rooij, J Clin Invest, 2007
miRNAs regulate inflammation, oxidative stress, apoptosis, and
angiogenesis in atherosclerotic plaques
Hulsmans M,
Faseb J, 2011
Human platelets contain an abundant array of miRNAs
Landry P, Nat Struct Mol Biol, 2009
Dicer/TRBP
pre-miRNA
Platelet
translation
Ago2
Ago2
Dicer
Exportin-5
mRNA
Drosha
pri-miRNA
mRNA
transcription
Translation
RISC
Target
degradation
RISC
TRBP
microRNAs
mature
miRNA
Target
inhibition
Megakaryocyte
Microparticle
Apoptotic bodies
Fibrinolysis
Platelet
aggregation
Gatsiou A Stellos K, Curr Vasc Pharmacol, 2012
MiRNA biogenesis machinery exists in platelets
Landry P, Nat Struct Mol Biol, 2009
Role of miRNAs in megakaryocytopoiesis
Gatsiou A Stellos K, Curr Vasc Pharmacol, 2012
PKA
cAMP
3’
Granules
secretion
3’
5’
MP
3’
PKAc
VAMP
v-SNARE
complex
5’
miR-223
VASP  VASP-P
Fibrinogen activation
Filopodia platelet
formation
5’
P2Y12
3’
miR-96
Cytoskeleton
ADP
miR-126
5’’
Binding of fibrinogen to
integrin α3β2
Platelet activation
E-box
per
Platelet
aggregation
Circadian
cycle
cry
3’
Platelet activation
Actin
CLOCK
BMAL1
Changes in
cytoskeleton and
platelet shape
KLH5
5’
miR-107
5’
3’
3’
CLOCK
miR-495
Gatsiou A Stellos K, Curr Vasc Pharmacol, 2012 In Press
Platelet-bound P-selectin and extent of myocardial infarction
Stellos K, J Thromb Haemost, 2010
Platelet microRNA-96 inhibits platelet activation through VAMP8/
endobrevin pathway
Kondkar A, J Thromb Haemost, 2010
Platelet microRNA-96 inhibits platelet activation through VAMP8/
endobrevin pathway
Kondkar A, J Thromb Haemost, 2010
Progenitor cell adhesion over immobilized platelets
SDF-1
Plt.
CD34+
cell
Flow Chamber
Stellos K, Circulation, 2008
Platelet-derived SDF-1 and JAM-A regulate differentiation of
CD34+ cells to late outgrowth proangiogenic cells
Fibronectin
Number of
endothelial colonies
Number of Endothelial
Colonies
B
C
Plts + JAM-A-Fc
Plts + Control-Fc
E
16
*
8
*
4
0
Collagen
25
Ø
Control
JAM-A
Fibronectin Control JAM-A-Fc
Immobilized proteins
Immobilized Platelets
n=3
20
15
*
*
*
10
*
5
0
IgG1
anti
JAM-A
antiSDF-1
IgG2b
antiCXCR4
haECs
Monocytes
CD34+ cells
Control-Fc
12
EPCs
D
JAM-A-Fc
IgG1 anti-SDF-1+
+IgG1 anti-JAM-A
F
mean tube length/µm
Collagen
Number of cells x 106
A
180
160
140
120
100
80
60
40
20
0
EPCs
haECs
CD34+ cells Monocytes
CD34+ cells
haEC
sEPCs (immob.JAM-A-Fc)
1,4
1,2
1,0
*
0,8
0,6
0,4
0,2
0
day 0
day 1
day 2
day 3
Stellos K, ATVB, 2010
Platelet-derived SDF-1 expression is increased in ACS
and correlates with the number of CD34+ progenitor cells
Stellos K, Eur Heart J, 2009
Apoptotic bodies carry miR-126 inducing SDF-1 Expression
Zernecke, Sci Signal, 2009
Apoptotic bodies/miR-126/SDF-1 induction pathway protects against
atheromatic plaque formation
Zernecke, Sci Signal, 2009
Circulating microRNA (miR) levels in coronary sinus and aortic blood.
De Rosa S et al. Circulation 2011;124:1936-1944
Copyright © American Heart Association
PKA
cAMP
3’
5’
3’
MP
3’
Granules
secretion
PKAc
VAMP
v-SNARE
complex
5’
miR-223
VASP  VASP-P
Fibrinogen activation
Filopodia platelet
formation
5’
P2Y12
3’
miR-96
Cytoskeleton
ADP
miR-126
5’’
Binding of fibrinogen to
integrin α3β2
Platelet activation
E-box
per
Platelet
aggregation
Circadian
cycle
cry
3’
Platelet activation
Actin
CLOCK
BMAL1
Changes in
cytoskeleton and
platelet shape
KLH5
5’
miR-107
5’
3’
3’
CLOCK
miR-495
Gatsiou A Stellos K, Curr Vasc Pharmacol, 2012 In Press
Thank you!
Team members
Carolin Amrhein, BTA
Stephan Gnerlich, MD
Katerina Gatsiou, BSc, MSc cand.
Victoria Panagiota, MD
Angela Paul, PhD
Annegret Perk, DVM
Saskia Sachsenmaier, MD
Kateryna Sopova, MD
Ria Tatsidou, BSc, MSc cand
Prof. Meinrad Gawaz (Tübingen)
Prof. Christoph Laske (Tübingen)
Prof. Andreas Zeiher (Frankfurt)
Prof. Stefanie Dimmeler (Frankfurt)
Prof. Ingrid Fleming (Frankfurt)
Prof. Alexandros Tselepis (Ioannina)
Supported by
•  University of Tübingen
•  German Research Foundation
•  Hirnliga e.V.
•  Goethe University of Frankfurt
•  August Scheidel Foundation
•  European Society of Cardiology (Initiative Grant)