Endothelial Integrity: KLF2 and the Endothelial Balancing Act
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1 Endothelial Integrity: KLF2 and the Endothelial Balancing Act Prof dr Anton J.G. Horrevoets Molecular Cell Biology and Immunology VU University Medical Center Amsterdam
2 Shear stress guides vascular remodeling Beneficial: outward remodeling, arteriogenesis Pathological: atherosclerosis, vascular stenosis
3 Focality of lesions correlates with flow patterns: Turbulence result in low shear stress and NFkB activation What is protecting the majority of the vasculature??? Flow imaging and computing: large artery hemodynamics. Steinman DA Ann Biomed Eng. 2005;33: Dai, G PNAS 2004;101, Copyright 2004 by the National Academy of Sciences
4 Endothelium aligns in direction of flow Arterial shear flow No Flow
5 SOM & hierarchical clustering of genes: digitized cellular phenotypes growth factors TGF-β VEGF b-fgf Shear stress NO Thrombin TNF-α IL-1α cytokines shear Dekker et al, Blood 2002
6 KLF2 localizes to atheroprotected regions In situ hybridisation: KLF2 Dekker et al. (2005) Am J Pathol. 167(2), p609 Davies et al. (1999) Trends Biotech. 17(9), p347
7 Transcription factor KLF2 * directly induces enos and Thrombomodulin * suppresses monocyte adhesion in presence TNFa number of events during 3 min mock TNF mock KLF2 KLF2 TNF
8 Augmented KLF2 results in endothelial differentiation 1000 genes affected: analysis by PubMed textmining Dekker, Boon et al. Blood 2006
9 Augmented KLF2 results in endothelial differentiation expression of 3 well-known endothelial marker genes Thrombomodulin enos Von Willebrand Factor Dekker, Boon et al Blood 2006
10 Shear induction enos and TM is KLF2 dependent Dekker Am J Pathol Van Thienen Card Res 2006
11 KLF2 promotes vwf storage and attenuates thrombin-induced vwf release Dekker, Boon et al Blood 2006
12 Mechanism of exocytosis of vwf containing Weibel-Palade bodies Rondaij et al. (2004)
13 KLF2 neutralizes effects TNFa on anti-coagulation Dekker,Boon Blood 2006
14 Endothelial KLF2 attenuates blood clotting under flow Lin Z, et al Circ Res 2005;96:e48
15 Effects of KLF2
16 Functional transcriptomics-promoter analysis deciphering the KLF2 transcriptional network
17 KLF2 and TGFbeta signaling are mutually exclusive in vivo detection by phosphospecific antibody: activated proteome Boon et al., ATVB 2007
18 KLF2 supresses TGFbeta signalling Smad4 c-jun Boon ATVB 2007
19 si-atf2 suppresses basal and inducible levels inflammatory genes Active phospho-atf2 only in human atherosclerotic lesion EC SELE CCL2 IL-8 VCAM1
20 Shear and KLF2 provoke a similar suppression of ATF2: this desensitizes NFkB response NFkB P300 ATF2 NFkB Inflammatory genes MCP-1, VCAM1, IL-8, PAI-1 Fledderus Blood 2008
21 KLF2 augments nuclear localization of anti-oxidant NRF2 This results in enhanced expression of multiple anti-oxidant enzymes Dai et al. Circ Res. 2007;101: Fledderus, Boon et al, ATVB 2008;28:
22 The KLF2-NRF2 axis in the shear stress genetic network 2 transcription factors control ~ 70% of shear controlled gene modules MAPK Shear stress Oxidant stress MEK5 Nrf2:Keap1 ERK5 + MEF2 KLF2 Nrf2 Keap1 transcriptional effects of shear stress
23 The KLF2-shear stress genetic network How a single transcription factor controls ~ 1000 genes ATF2 Smad NRF2 TM enos KLF2
24 The KLF2-shear stress genetic network How a single transcription factor controls ~ 1000 genes Anti-inflammation ATF2 Anti-fibrosis Smad TM Anti-coagulation Anti-oxidant NRF2 enos Anti-vasoconstriction KLF2
25 How can we tip this balance? Onset or Oscillatory Shear stress NFκB AP-1 KLF2 Nrf2 NFκB AP-1 Prolonged laminar Shear stress KLF2 Nrf2 Inflammation Coagulation Anti-inflammatory Anti-coagulant Inflammation Coagulation Anti-inflammatory Anti-coagulant
26 Kinome analysis: Actin rather than MAPK Symbol Phosphosite Bayes.p Fold Symbol Phosphosite Bayes.p Fold FAK Y PKCg T FAK S Abl Y CDK1/2 T14+Y RSK1/2 S363/S Hsp27 S Src Pan-specific FKHRL1 T HO2 Pan-specific Hsp27 S ATF2 T51+T CDK7 Pan-specific p38a Pan-specific HspBP1 Pan-specific PKCb2 T c-jun S STAT5A Y Crystallin ab S S6Ka T IRAK4 Pan-specific Bad S PKCq S EGFR Pan-specific Ksr1 Pan-specific PKCg Pan-specific Rb S FAK Y PP6C Pan-specific Erk4 Pan-specific Tau S Kit Y EGFR Y ERK5 T218+Y Boon, Blood 2010
27 KLF2 fibers localize on the basal side of endothelium and contain phosphomyosin
28 KLF2 essential for shear fiber induction and JNK suppression siklf2
29 KLF2 induced shear fibers are ROCK independent, mdia dependent Y27632 Lenti-KLF2 shmdia Vinculin F-Actin Nuclei Thomas Leyen, 2010
30 Absence of shear fibers leads to improved endothelial cell alignment to flow Non-targeting shrna shdiaph Number of cells (% of total number) ** Non-targeting shrna shdiaph2 shmdia <10 o 10 o -20 o 20 o -30 o 30 o -40 o >40 o Unaligned Flow Cell angle relative to flow direction
31 Shear fibers are important for firm attachment to extracellular matrix EC mock EC KLF2
32 Shear fibers needed for firm adhesion under flow
33 Cell resistance to flow is directly coupled to anti-inflammatory effect through actin cytoskeleton NRF2 Firm Adhesion Boon, Blood 2010
34 Shear Stress in a pill?!
35
36 Statins induce enos and thrombomodulin through KLF2 (involves MAPK ERK5 and Rho) Van Thienen, Cardiovasc. Res 2006
37 Is shear stress a drugable target? Lenti-KLF2 Statins Resveratrol
38 Resveratrol activates SIRT1, CPTH2 inhibits GCN5 Both induce KLF2 and shear fibers, MEF2 dependent 50 μm Resveratrol 72h 72h CPTH2 0,2 mm 10 μm Thomas Leyen 2010
39 Possible pathway for small moleculemediated KLF2 expression involve PGC1a Sirtinol AMPK Resveratrol SIRT1 Ac SRT1720 GCN5 SRC3 CPTH2 PGC1α PGC1α MEF2 MEF2 site KLF2
40 An integrated KLF2 module for vascular protection Resveratrol mdia Ingber Tensegrity website
41 Endothelial Balancing Act: Actin Triple Crown by Kenneth Snelson Ingber, D. E. J Cell Sci 2003;116:
42 The protective endothelial shear response Flow-induced KLF2 is a central mediator of endothelial phenotype -induction of enos and thrombomodulin -promotes activity of anti-oxydant transcription factor NRF2 -focal adhesion capped shear fibers -results in firm adhesion of EC to substratum - less alignment (flow resistance) - suppresses SMAD, c-jun and ATF2 activity / antiinflammatory The KLF2/shear modules can be modified by small molecules -Resveratrol induces KLF2 and shear fibers,mediated through SIRT1 and MEF2 -CPTH2 induces shear fibers indicating a role for PGC1a acetylation
43 Acknowledgements VUmc/AMC Reinier Boon Rob Dekker Joost Fledderus Ruud Fontijn Jakub Rohlena Oscar Volger Thomas Leyen Cansu Yildirim Tineke van der Pouw Kraan AMC Amsterdam Perry Moerland Ed van Bavel Allard van der Wal Stephan Schirmer Niels van Royen VUmc Amsterdam Victor van Hinsbergh Geerten van Nieuw Amerongen Univ Maastricht-Pathology Mat Daemen Erik Biessen Univ Leiden-LACDR Johan Kuiper Theo van Berkel Univ Leiden-MCB-II Lia Pardali Peter ten Dijke Sanquin Research Amsterdam Jaap van Buul Peter Hordijk Goethe University Frankfurt Reinier Boon Stefanie Dimmeler Nederlandse Hartstichting Molecular Cardiology Program Genomics Genomics
Education University (Masters degree): Medical Biology, University of Amsterdam, Amsterdam, the Netherlands
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