Impact of the American Heart Association's Heart Health in ...
Presentation Slides - My American Heart
Transcript of Presentation Slides - My American Heart
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The Renin-angiotensin System in Obesity and Vascular Diseases
Lisa A. Cassis, PhD
Professor and Chair
Department of Molecular and Biomedical Pharmacology
University of Kentucky
No relevant financial relationships exist.
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Harriett Dustan
• Pioneer in clinical cardiovascular research
• 1st person to give sodium nitroprusside to humans,
• Thiazide diuretics potentiate blood pressure lowering of other antihypertensives,
• Definition of hemodynamics of primary aldosteronism,
• Pathophysiology of obesity-related hypertension
In Memoriam, Circulation 100:2122-2123, 1999
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Acknowledgments: Lab/Trainees
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The Ever Evolving RAS Angiotensinogen
Angiotensin I (1-10)
Renin
Angiotensin II (1-8)
ACE
Angiotensin III (2-8)
Aminopeptidase A
Angiotensin IV (3-8)
Aminopeptidase N
Ang1-9 Ang1-7 ACE2 ACE
Prorenin ?
(Pro)Renin Receptor
Activates Renin
Signals
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Research Program
Angiotensin II
Adipose Tissue Atherosclerosis
AAA Hypertension
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EC
Muscle
Adventitia
Adipose
Ao
Ao
Ao
Ao
Ao
Ao
Ao
Ao
Ao Ao Ao
Ao
Ao
Ao
Ao
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Expression of RAS components during adipocyte differentiation
Undiff4hrs 8hrs 12hrs D1 D2 D3 D4 D5 D6 D7 D8 D9 D100.0
0.5
1.0
1.5
2.0
*
*
*
*
**
* *
*,P<0.05
AO
/18S
Undiff 4hrs 8hrs 12hrs 1d 2d 3d 4d 5d 6d 7d 8d 9d 10d0.00
0.01
0.02
0.03
0.04
**
AT
1a/1
8S
*
*,P<0.05
Angiotensinogen
AT1 receptor
ACE2
UD 4hrs8hrs12hrs D1 D2 D3 D4 D5 D6 D7 D8 D9 D100.000
0.025
0.050
0.075
0.100
***
*
*,P<0.05
AC
E2/1
8s
Undifferentiated 1 2 3 4 5 6 7 8 9 10
Cocktail
Gupte et al., AJP 295: R781-8, 2008
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Prevalence Obesity* Trends Among U.S. Adults
(*BMI 30)
No data <10% 10-14% 15-19% 20-24% 25-29% >30%
Source: CDC, Behavioral Risk Factor Surveillance System, February 2010
1999 1990 2009
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OBESITY
↑Angiotensin II
Hypertension
↑Angiotensinogen (AGT)
Frederique Yiannikouris, PhD
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Neocassette Exon 2
Lox P Lox P FRT FRT
Lox P Lox P
Exon 3
Flp
Ap2-Cre
Lox P flanked allele
Deleted allele
Lox P
FRT
Exon 2 Exon 3 Neo
Lox P
Exon 3
a
b
c
0
10
20
30
40
Day 0 Day 8
Agtfl/fl
AgtaP2
*
*,**
**A
GT
(n
g/m
l)
AGT mRNA abundance AGT protein
Agtfl/fl, wild type, AgtaP2 adipocyte AGT deficient
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Adipocyte AGT deficiency has no effect on body weight, fat mass, or glucose tolerance
A
0
10
20
30
40
50
LF HF
** *,**
*
AgtaP2
Agtfl/fl
Fat
mass (
% l
ean
)
0
10
20
30
40
50
60
70
80
LF HF
** **
Agtfl /fl
AgtaP2
Lean
mass (
% B
W)
B
0 2 4 6 8 10 12 14 160
Agtfl/fl, LF
AgtaP2, LF
Agtfl/fl, HFAgtaP2, HF
*****
* ***
***
20
30
40
50
Time
Bo
dy w
eig
ht
(g)
Agtfl/fl = controls AgtaP2 = Adipocyte AGT deficient
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Adipocyte deficiency of AGT ablates obesity-hypertension
0
LF HF
Agtfl/fl
AgtaP2 *
**
100
110
120
130
140
SB
P (
mm
Hg
)
Hypertension, in press, 2012
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Reductions in plasma AngII in obese adipocyte AGT-deficient mice are paralleled by reduced adipose AngII content
0
50
100
150
200
250
300
Agtfl/fl
AgtaP2
LF HF
*
**
An
g II (p
g/m
l)
0
5000
10000
15000
20000
25000
Agtfl/fl
AgtaP2
LF HF
An
gII (
pg
x t
ota
l fa
t
ma
ss
)
PLASMA ADIPOSE TISSUE
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Summary
• Deficiency of AGT in adipocytes prevents obesity-induced increases in plasma AngII and obesity-related hypertension
• Tissue production of AngII (e.g., adipose) can be a significant source of circulating AngII in the setting of obesity and in the development of obesity-induced hypertension
Hypertension, in press, 2012
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OBESITY
↑Angiotensin II (AGT)
Undiff 4hrs 8hrs 12hrs 1d 2d 3d 4d 5d 6d 7d 8d 9d 10d0.00
0.01
0.02
0.03
0.04
**
AT
1a/1
8S
*
*,P<0.05
Why do adipocytes have AT1aR? What does AngII do to an adipocyte? Is this influenced by obesity and does it contribute to obesity-associated diseases?
Kelly Putnam
Endocrinology, epub ahead of press, 2012
Adipocyte AT1aR
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Liver Kidney Heart Brain Spleen BAT WAT0.0
0.1
0.2
AT1aRfl/fl
AT1aRaP2
*
* *
0.2
1.2
AT
1a
R:1
8s
X FLPE
LoxP3
FRT
LoxP1
Exon 3 AT1aRfl/fl
Exon 3 Neocassette
FRT FRT
LoxP1 LoxP2 LoxP3
X aP2-Cre
AT1aRaP2
Floxed AT1aR Gene
LoxP1-3
Adipocyte deletion of the AT1aR
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Adipocyte AT1aR deficiency has no effect on the development of obesity
0 5 10 15
20
40
60
AT1aRaP2 HF
AT1aRfl/fl HF
AT1aRaP2 LF
AT1aRfl/fl LF
Weeks on diet
We
igh
t (g
)
0 AT1aRfl/fl
AT1aRaP2
AT1aRfl/fl
AT1aRaP2
0
20
40
60
80
100
% Lean mass
% Fat mass
LF HF
* *
% o
f b
od
y m
as
s
, but……
0
1000
2000
3000
4000
5000
6000
7000
0
20
40
60
80AT1aR
fl /fl LF
AT1aRaP2
LF
Adipocyte size (m2)
# o
f c
ell
s
LF HF0
1000
2000
3000
4000AT1aR
fl /fl
AT1aRaP2
***
Me
an
ad
ipo
cyte
siz
e (
m2)
AT1aRfl/fl
AT1aRaP2
0.0
0.2
0.4
0.6
0.8
1.0
*
Ab
so
rb
an
ce
(5
10
nm
)
AT1aRfl/fl
AT1aRaP2
0
200
400
600
*
PP
AR:1
8s
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Summary
• Adipocytes have AT1aR, but they play no major role in the development of obesity
• In lean mice, deficiency of AT1aR on adipocytes decreases adipocyte differentiation, resulting in hypertrophy of remaining adipocytes
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OBESITY
ACE2 AngII Ang-(1-7)
UD 4hrs8hrs12hrs D1 D2 D3 D4 D5 D6 D7 D8 D9 D100.000
0.025
0.050
0.075
0.100
***
*
*,P<0.05
AC
E2/1
8s
X
Sean Thatcher, PhD Assistant Professor
Manisha Gupte, PhD
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Hypertension prevalence is greater in men than women before menopause: Are females protected
against obesity hypertension?
Age Men (%) Women (%)
20-34 9.2 2.2
35-44 21.1 12.6
45-54 36.2 36.2
55-64 50.2 54.4
65-74 64.1 70.8
75 and older 65.0 80.2
All 31.8 30.3
CDC
Menopause
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0 5 10 150
515
20
25
30
35
40
45
50
55Male, LFMale, HF
Female, LF
Female, HF
*
**
**
**
* *
* *
**
**
*
Bo
dy w
eig
ht
(gm
)
Male Female0
5
10
15
20
25LF
HF *
*,**
**
Fat
mass (
g)
Female mice gain more weight and fat mass than males
65%
97%
86%
236%
*, P<0.05 compared to LF
*, P<0.05 compared to LF **, P<0.05 compared to male Male Female
0
50
100
150LF
HF **
**
SB
P N
igh
t (m
mH
g)
but are protected from obesity-hypertension
Arteriosclerosis, Thrombosis and Vascular Biology 32:1392-9, 2012
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The AngII/Ang-(1-7) balance is different between obese males and females, and ACE2 deficiency promotes
hypertension in both sexes
Male Female0.0
0.2
0.4
0.6
0.8 LF
HF
***
**
Pla
sm
a A
ng
-(1-7
) (n
g/m
l)
Male Female0
50
100
150
200Ace2
+/+, HF
Ace2-/-
, HF
*,****
*
SB
P N
igh
t (m
mH
g)
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Summary
• ACE2 is important in regulating the AngII/Ang-(1-7) balance in the development of obesity-hypertension
• Females rule!, they are protected against obesity-hypertension potentially through an ACE2-dependent mechanism
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Research Program
Angiotensin II
Adipose Tissue Atherosclerosis
AAA Hypertension
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AAA
• 13th leading cause of death in the United States
• Risk factors – Male Gender
– Smoking
– Age >65
– Family history
– Hypertension
– Obesity
• No pharmacologic treatments for AAA • Surgical repair is the only therapeutic option to prevent
rupture (> ~ 5.0 cm)
Allison et al. J Vasc Surg 2008; 48:121-7, Golledge et al. Circulation 2007; 116:2275-2279.
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Angiotensin II
28 days Osmotic mini-pump
apoE-/- LDLr-/-
AAA
Atherosclerosis
AngII-induced Vascular Pathology
Daugherty A, Manning MW, Cassis LA. J Clin Invest. 2000 Jun;105(11):1605-12.
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Risk Factors: Effects of Male Gender
Hypothesis:
Sex hormones mediate gender differences in AngII-induced vascular diseases by regulating the AT1a receptor
Xuan Zhang, PhD
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Androgen is the primary regulator of AAA susceptibility in male mice through regulation of
aortic AT1aR
Sham Orx
% A
AA
Incid
ence
0
20
40
60
80
100
*
Male Female
% In
cid
ence
0
20
40
60
80
100
intact 1 week 5 weeks 1 week 5 week0.0
0.1
0.2
0.3
0.4
0.5
0.6
thoracic
abdominal
Castration Castration+DHT
AT
1a/1
8S
Male/Female AAA susceptibility Testosterone is the mediator
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Aortic Development
Adapted from Majesky M. ATVB 2007
AR
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Can we turn a female into a male with enhanced
AAA susceptibility by exposing her to testosterone
early in life?
Day 1
Testosterone (400 µg/mouse)
or Vehicle
10-12 weeks
•Aortic gene expression
•AngII infusion
Question
Circulation Research 25:373-85, 2012.
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Neonatal testosterone strikingly promotes AngII-induced AAAs in adult female mice
500 750 10000
20
40
60
80vehicletestosterone
AngII infusion rate (ng/kg/min)
AA
A in
cid
en
ce
(%
)
*,**
A
C
B
vehicle testosterone
saline AngII0.0
0.5
1.0
1.5
2.0
2.5vehicletestosterone
Maxim
al exte
rnal
ab
do
min
al ao
rtic
dia
mete
r (m
m)
*,**
*
vehicle testosterone0.00
0.01
0.02
0.03
0.04
0.05thoracic
abdominalA
T1aR
/18s r
ati
o
ApoE-/-
*,**
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Summary
• Testosterone has pronounced effects during development to influence the vasculature.
• AT1a receptors are a target of testosterone in smooth muscle cells to influence vascular remodeling in aneurysm formation.
• Vascular disease is sexually dimorphic.
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Acknowledgments: Grant Support
• NIH HL73085 (LAC)
• NIH HL107326 (LAC)
• NIH P01 HL080100 (AD, LAC)
• NIH P42 ES007380 (BH, LAC)
• NIH T32 DK007778 (LAC)
• NIH P20 GM103527 (LAC)
• AHA: 0815419D (MG), 11PRE6760002 (KP), Pre0815513D (XZ), 12PRE12050430 (RS)
Alan Daugherty