Critical Role of RAAS in Vasculoprotection: New Science

1
Critical Role of RAAS in Vasculoprotection New
Science
2
New aspects of RAAS

• ACE homologues
• ACE2
• Soluble ACE
• ACE substrates
• Ang (17)
• Ang (19)
• N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP)
• Amyloid ß-protein
• Formation of Ang II by non-ACE peptidases
• ACE signal transduction pathway

RAAS renin-angiotensin-aldosterone system
Fleming I. Circ Res. 200698887-96.
3
RAAS Current and potential targets
Angiotensinogen
Renin
ACE2
Ang I
Ang (19)
NEP
CAGECathepsin GChymase
ACE
ACE
ACE
ACE2
Ang (17)
Ang (15)
Ang II
AT1R
AT2R
AT3R
AT4R
AT(17)R
masR
Aldosterone
Adapted from Ferrario CM, Strawn WB. Am J
Cardiol. 200698121-8.Duprez DA. J Hypertens.
200624983-91.
4
Impact of ACEI on ACE signaling pathway
ACE
ACE inhibitor
NH2
Extracellular
Clinical significance of this pathway is under
investigation
MKK7
Cytosol
CK2
JNK
COOH
cJun
P
JNK
P
cJun
P
cJun
P
P
cJun
cJun
P
cJun
P
cJun
Nucleus
AP-1
Gene expression(ACE, COX-2)
Fleming I et al. Physiology. 20052091-5.
5
ACE metabolism
Actions of ACE, kininase II
Asp-Arg-Val-Tyr-lie-His-Pro-Phe-His-Leu
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg
Angiotensin I
Bradykinin
Angiotensin II His-Leu
Bradykinin 17 Phe-Arg
Erdös EG. FASEB J. 2006201034-8.
6
ACEI mechanism of benefit Reduction in clinical
events
Bradykinin
Angiotensin I
ACE/Kininase II
Degradation products
Angiotensin II
ACE inhibitors
?Bradykinin
?Angiotensin II
?BP ?Oxidative stress ?Endothelial
dysfunction ?Glucose metabolism ?Plaque
growth ?Fibrous cap stability ?MMP activity
?Nitric oxide
Reduction inclinical events
MMP matrix metalloprotease
Fleming I et al. Physiology. 20052091-5.
7
Renin inhibition prevents LVH in animal models
9-week-old double transgenic rats (untreated died
by week 8)
Cardiac hypertrophy index
LV wall thickness
0.40
5
0.35
4
0.30
cm
mg/g
3
0.25
2
0.20
Valsartan
Aliskiren
Valsartan
Aliskiren
10
1
0.3
3
10
1
0.3
3
mg/kg/d
mg/kg/d
P lt 0.05 vs other groups P lt 0.05 vs valsartan
10 mg/kg/d
Pilz B et al. Hypertension. 200546569-76.
8
Demonstrated benefits of AT1R blockade

• Blood pressure
• Heart failure symptoms
• Diabetic renal disease progression
• Stroke

Strauss MH, Hall AS. Circulation. 2006114838-54.
9
AT1R blockade upregulates both Ang II levels and
AT2R expression
Both physiologic and pathologic effects have been
proposed for AT2R stimulation
Ang I
Ang I
ACE
ACE
Ang II
Ang II
ARB
ARB
AT1
AT4
AT1
AT4
AT2
AT2
Vasodilation
Hypertrophy Inflammation
Strauss MH, Hall AS. Circulation. 2006114838-54.
10
Postulated role of AT2R and MMP-1 in plaque
destabilization
Ang IIARB AT1 AT2
Destabilization ? Rupture ? ACS
Endothelium
?MMP-1
Extracellularmatrix
Intracellular inflammation
Leukocyteactivation
Vascular smooth muscle cells
Strauss MH, Hall AS. Circulation. 2006114838-54.
11
AT2R mediates cardiac myocyte enlargement during
pressure overload
Agtr2/Y AT2R-deficient mice and wild-type mice
200
160
Wild-type

Left ventricular mass(mg)
120
Agtr2/Y
80
40
0
Before
2 weeks
10 weeks
Aortic-banded mice Control (sham-operated) mice

P lt 0.05
Senbonmatsu T et al. J Clin Invest.
2000106R25-9.
12
Sustained decrease in PAI-1 antigen over time
with ACEI vs ARB
N 20 obese patients with hypertension and
insulin resistance
20
10
? PAI-1antigen(ng/mL)
0
-10
-20
1
3
4
6
Weeks
ACEI (ramipril)
ARB (losartan)
BMI 33.4 ramipril, 31.2 losartanP 0.043,
drug time interaction
Brown NJ et al. Hypertension. 200240859-65.
13
ACEIs and bradykinin oppose Ang II effects
Bradykinin
ACEI
Ang I
-
-
ACE

B2R
Inactive peptides
ACEI
Ang II
Vasodilation NO Prostaglandins EDHF tPA
AT1R
Vasoconstriction Aldosterone secretion Fibrosis Pr
oliferation Oxidative stress Matrix
formation Inflammation
Adapted from Ferrario CM, Strawn WB. Am J
Cardiol. 200698121-8.Adapted from Murphey L et
al. Eur Heart J Suppl. 20035(A)A37-41.
14
Ang II effect in target organ damage
VSMC
Angiotensinogen
Fat cells
Renin
Aldosterone(Adrenal/CV tissues)
Angiotensin I
ACE
?BP
Angiotensin II
Reduced baroreceptor sensitivity
Stroke
HF
Kidneyfailure
McFarlane SI et al. Am J Cardiol.
200391(suppl)30H-7.
15
Potential role of RAAS activation in metabolic
syndrome and diabetes
Obesity
RAAS activation
Skeletal muscle
Pancreatic ß cells
?MetS
?T2DM
MetS metabolic syndrome T2DM type 2 diabetes
Adapted from Henriksen EJ, Jacob S. J Cell
Physiol. 2003196171-9.Paul M et al. Physiol
Rev. 200686747-803.
16
RAAS activation in obesity
Circulating RAAS, N 38 menopausal women

12
90

9
60
Renin(ng/l)
Aldosterone (ng/l)
6
30
3
0
0
Lean
Obese
Lean
Obese
60
0.10

45
ACE(U/l)
Ang II(nmol/l)
30
0.05
15
0
0.00
Lean
Obese
Lean
Obese
P lt 0.05
Engeli S et al. Hypertension. 200545356-62.
17
RAAS activation contributes to obesity-related
hypertension
Obesity
?Leptin
Renal medullary compression
?RAAS activation
Sodium reabsorption
Renal vasodilation
?SNS activation
Volume expansion
Arterial hypertension
SNS sympathetic nervous system
Sharma AM. Hypertension. 20044412-19.
18
ACEIs Potential mechanisms of improved glucose
metabolism
Angiotensin I
Bradykinin
ACE/Kininase II
Degradation products
Angiotensin II
ACE inhibitors
?Angiotensin II
?Bradykinin
?Nitric oxide
?Skeletal muscleblood flow ?Glucose metabolism
Henriksen EJ, Jacob S. J Cell Physiol.
2003196171-9.
19
Role of Ang II in insulin resistance Focus on
signaling pathways
BK
NO
BK2 receptor

?NO
Glucose transport
Akt1

Insulin receptor



GLUT-4 trans-location
PI3-K
IRS-1
Insulin

-
GLUT-4 biosynthesis
-
GLUT-4
AT1 receptor
Ang II
Adapted from Henriksen EJ, Jacob S. J Cell
Physiol. 2003196171-9.
20
ACEIs improve glucose uptake in peripheral tissue
KK-Ay mouse model of T2DM
500

400
Evidence for bradykinin-mediated effect
Rate constant of 2-3HDG uptake
300

200
100
0
Control
Temocapril
Temocapril HOE 140
Temocapril L-NAME
HOE 140
L-NAME
P lt 0.05 vs controlP lt 0.05 vs temocaprilHOE
140 bradykinin B2 receptor blockerL-NAME
nitric oxide synthase inhibitor
SOLEUS
Schiuchi T et al. Hypertension. 200240329-34.