angiotensin converting enzyme 2 (ace2)/ang-(1-7) axis in
TRANSCRIPT
Angiotensin converting enzyme 2 (ACE2)/Ang-(1-7) axis in hypertension and cardiovascular disease:
bench to bedside
Gavin Y. Oudit, MD PhD FRCPCAssociate Professor, University of Alberta
Clinician-Scientist, Mazankowski Alberta Heart InstituteCanada Research Chair in Heart Failure
May 27th, 2016
10th Oriental Congress of Cardiology
Shanghai, China
Step-wise, incremental, reduction
in 1-year mortality with
combination neurohumoral
blockade in patients with systolic
heart failure and moderate-to-
severe symptoms
Circulation 1990
239 patients with severe heart failure (all in NYHA class IV)
ACE2 ACE2
Ang II and
AT1 R activity
Ang-(1-7) and
Mas R activity
Cardiovascular and
Renal Disease
Cardiovascular and
Renal Protection
Ang II and
AT1 R activity
Ang 1-7 and
Mas R activity
ACE2 as a negative regulator of the RAS illustrating the opposing
roles of Ang II/AT1 receptor and Ang 1-7/Mas receptor systems
Clinical Trials of ACE2 as a novel therapy for
CV, Lung and Kidney Diseases
Types of Adverse Ventricular Remodeling:
Burden from Hypertension and Coronary Artery Disease
Hill and Olson
NEJM, 2008
WT
AC
E2
-/-
sham 3days 1 week
Post-MI
0 1 2 3 4 5 6 7 14 21 2820
30
40
50
60
70
80
90
100
110S
urv
iva
l (%
)
Days
WT
ACE2-/y
LAD Ligation
Adverse Remodeling in Response to Myocardial Infarction
in ACE2KO mice
2
3
4
5
6
7
0
10
20
30
40
50
60
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
Post-MI
LV
ED
D (
mm
)
Post-MI
Sham 1 wk 4wks
WT
ACE2-/-
FS
(%
)
Sham 1wk 4wks
Sham 1wk post-MI
+dP
/dt
(mm
Hg/s
)
P <0.01
*
**
Aortic Banding
Experimental Model of Biomechanical Stress
(Pressure -Overload)
Pressure
overload
Compensated
Hypertrophy
Wall Thickness
contractility
Transition Phase
LV dilation
Contractility
Decompensation
Severe LV dilation
Contractility
Norrmalized Wall Thickness
6 wks 9-12 wks3 wk
Adverse Remodeling in Response to Biomechanical Stress
in ACE2KO mice
Circulation 1990
239 patients with severe heart failure (all in NYHA class IV)
Human Explanted Heart (Adult/Pediatric)/Non-Failing Donor Hearts
Atrial/VentricularTissue Retrieval
and Storage
ABACUS Cardiovascular Science Integrated Research Core Laboratory
Isolation/Culture of Cardiomyocytes and Fibroblasts
HistologyCoronary Isolationand Study
Pericardium/Valve Isolation
VFibrillation Optical Mapping
• “Healthy” Donor Hearts for Research (HOPE Program)• LVAD Apical Core Samples
ACE2 is an X-linked gene
Circ HF 2014
ACE2, ACE, Ang-(1-7), and Ang-II Protein Expression in 5 Groups of
Rats 4 Weeks After ACE2 Gene Transfer (12 wks after STZ)
Cardiac-specific vs systemic over-expression of ACE2
Recombinant human ACE2 partly normalizes the hypertensive phenotype
and restores the balance in plasma Ang II–Ang-(1–7) in the SHR model
Central role of the angiotensin-converting enzyme 2 (ACE2)/Ang 1–7 axis in heart failure: nonischemic cardiomyopathy, myocardial infarction (MI), diabetic cardiomyopathy, and obesity-
associated cardiac dysfunction.
Vaibhav B. Patel et al. Circ Res. 2016;118:1313-1326
Copyright © American Heart Association, Inc. All rights reserved.
LC-MS based RAS-Fingerprinting: RAS-Fingerprints 10 min after spiking 1800 pg/ml Angiotensin 1-10 to full blood at 37 C
Control 4 μg/ml Lisinopril
5 μg/ml rhACE2Control
rhACE2 + Lisinopril Control
Normalization of an activated RAS axis by rhACE2
in patients with acute HF (AHF)
JCI 2010
alternative source for Ang II production in human atrial and
ventricular tissue: CHYMASE
Elevated myocardial Ang II peptide levels and chymase activity
despite ACE inhibition in explanted human hearts with DCM.
NFC=Non-failing controls (n=12); DCM=Dilated cardiomyopathy (n=25; n=15 with ACEi; n=10 without ACEi)
Phase IIa
GSK2586881
0.4 mg/kg I.V.
BID for 3 days
vs Placebo I.V.
BID for 3 days
Acknowledgements1. Dr. Jiuchang Zhong, Shanghai 2. Dr. Zamaneh Kassiri, Edmonton
3. Dr. Josef Penninger, Vienna 4. Dr. Gary Lopaschuk, Edmonton