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Shear stress and atherosclerosis

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Presentation on theme: "Shear stress and atherosclerosis"— Presentation transcript:

1 Shear stress and atherosclerosis
Jun-ichi Abe, MD, PhD, FAHA Department of Cardiology Division of Internal Medicine

2 What is shear stress?

3 Shear stress and atherosclerosis
Malek AM, Alper SL, Izumo S. JAMA. 1999;282:

4 Steady laminar flow vs. Disturbed flow
Disturbed flow/TNF ? ? Survival Increased NO Apoptosis Inflammation

5 p160 Bcr is Present in Rat and Human VSMC
MAPKs Stress, inflammatory cytokines Rac, cdc42 MEKK1 MKK4/7 DLK MLK2/3 ASK1 TRAF2/6 c-Jun, ATF2 MEKK2, 3 JNK1,2,3 GCK Pak1 MST1 Shear stress Oxidative stress Src MEF2A,C ERK5/BMK1 MEK5 MEKK2, 3 Stimuli Mitogens c-Raf-1 MEK1/2 Ras p90RSK Elk1 NHE-1 ERK1/2 MEKKKs MEKKs ATF2, CHOP, MEF2C p38 MKK3/6 MEKs MAPKs Substrates p160 Bcr is Present in Rat and Human VSMC p210 Bcr/Abl p160 Bcr IB: Bcr Rat aortic SMC CHO Rat 1 K562 Endothelial cells Human aortic SMC

6 Steady laminar flow activates ERK5 activity in endothelial cells
(Yan C et al., J Biol Chem, 1999)

7 Transcriptional activation
Structure of ERK5 / BMK1 MEK5 binding site Arginine (R) rich domain P P N ATP TEY R NLS Pro rich Transcriptional activation ERK5 / BMK1 C Cytosolic targeting Kinase domain P P N TEY ERK1/ p42/p44 C PPAR binding site Transactivation domain

8 Akaike M et al., Mol. Cell. Biol. 2004 24(19):8691-8704.
Activated MEK5 C PPARg binding site T Y N Kinase domain P Transactivation domain ERK5 T Y N C Kinase domain C T Y N Kinase domain P DBD Hinge-helix1 AF-1 AF-2 Hinge-helix1 DBD AF-1 AF-2 Helix3-5 Helix12 SMRT PPARg1 SMRT Akaike M et al., Mol. Cell. Biol (19):

9 Flow-induced anti-inflammatory response
Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2 : Flow-dependent expression of KLF2 & its regulation by a MEK5/ERK5/MEF2 pathway.  Parmar et al., JCI 2006 KLF2 expression A B

10 What is SUMO?

11

12 SUMO Substrate Higher-order chromatin structure Protein-protein
interaction Antagonism of ubiquitination SUMO Subnuclear localization Nuclear pore complex shutting Substrate Transcription factor activity Integrity of PML nuclear bodies Regulation of DNA binding Verger A, et al. EMBO Rep Feb;4(2):

13 SUMOylation system

14 ERK5-SUMOylation SUMOylation regulates transcriptional
activity without affecting kinase activity. MEK5 binding site Arginine (R) rich domain Transactivation domain SUMO P P N Pro rich C ATP TEY ERK5 / BMK1 R NLS Cytosolic targeting Kinase domain Flow & MEK5 H2O2 & AGE SUMO Transactivation Domain Transactivation Domain Woo CH et al., Circ Res Mar 14;102(5):

15 Transrepression activity
SENP2 de-sumoylation enzyme

16 SENP2 and atherosclerosis formation (1)
D-flow NLC (WT)/Ldlr-/- Senp2+/-/Ldlr-/- S-flow NLC (WT)/ Ldlr-/- Senp2+/-/ Ldlr-/- NLC (WT)/ Ldlr-/- Senp2+/-/ Ldlr-/- Heo KS, et al. Circ Res. 2013, Mar 15;112(6):

17 Shear stress and atherosclerosis
D-flow Heo KS, Chang E et al. Circ Res 2013, in press. ? SENP2 SUMO SUMO

18 p90RSK SENP2 Nuclear export ERK5-SUMO p53-SUMO N- -C Disturbed flow
Heo KS, et al. J Clin Invest. 2015 Mar 2;125(3): Disturbed flow (Pro-atherogenic flow) Nuclear export SENP2 131 300 P 386 N- -C NLS NES NES NES NLS ERK5-SUMO p53-SUMO

19 D-flow induced SENP2 nuclear export via SENP2 T368 phosphorylation
b Ad-SENP2 WT Ad-SENP2-T368A Heo KS, et al. J Clin Invest. 2015 Mar 2;125(3):

20 D-flow increased SENP2 T368 phosphorylation
Heo KS, et al. J Clin Invest. 2015 Mar 2;125(3):

21 Detecting ERK5 transcriptional activation
80 vector 70 CA-MEK5 pBind-ERK5 60 CA-MEK5 ERK5 50 Relative ERK5-Luc Activity Gal4 40 ** Gal4/Gal4/Gal4/Gal4/Gal4 TATA Luci. 30 ** Mammalian one-hybrid assay 20 10 10 30 100 H2O2 (µM)

22 ERK5 transcriptional activator
Le NT et al. J Immunol Oct 1;193(7):

23 Antimalarial drugs During World Word II, about four million US soldiers took an antimalarial drugs to prevent malaria, and they found that lupus or arthritis showed fewer symptoms. However, how antimalarial drugs can inhibit inflammation remains largely unknown.

24 Akaike M et al., Mol. Cell. Biol. 2004 24(19):8691-8704.
Activated MEK5 C PPARg binding site T Y N Kinase domain P Transactivation domain ERK5 T Y N C Kinase domain C T Y N Kinase domain P DBD Hinge-helix1 AF-1 AF-2 Hinge-helix1 DBD AF-1 AF-2 Helix3-5 Helix12 SMRT PPARg1 SMRT Akaike M et al., Mol. Cell. Biol (19):

25 CQ releases SMRT1 (trans-repression) via ERK5
Le NT et al. J Immunol Oct 1;193(7):

26 D-flow D-flow S-flow Apoptosis  Inflammation  p90RSK p53 SENP2
Senp2+/+/Ldlr-/- Senp2+/-/Ldlr-/- P Ad-DN-p90RSK (K94A/K447A) p90RSK Aortic D-flow P -T368 Bcl-2 p53 S-flow Thoracic and abdominal SENP2 ERK5-SUMO p53-SUMO P ERK5 MEF2 Apoptosis  KLF-2-eNOS Inflammation 

27 Acknowledgement Abe lab U of R UCSF The University of Manchester
Nhat-Tu Le Kyung-Sun Heo Ikjae Shin Kyung-Ae Ko Carolyn McClain Yuki Ishizawa Yuichiro Takei Chang-Hoon Woo Masashi Akaike U of R Craig Morrell Sara Ture Orazio Silvano Keigi Fujiwara Tamlyn Thomas Edward Yeh UCSF Jack Taunton The University of Manchester Xin Wang

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