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