This document discusses newer concepts in the renin-angiotensin-aldosterone system (RAAS), including tissue and cardiac RAAS. It describes how the RAAS was traditionally viewed as circulating in the bloodstream, but is now understood to also exist locally in tissues. Local tissue RAAS can generate angiotensin II independently of circulating RAAS through local synthesis of angiotensinogen and renin. Inhibition of tissue RAAS provides benefits like reducing endothelial dysfunction, vascular damage, and organ damage in the heart and kidneys.

1. Newer Concepts in RAAS:
Tissue, and Cardiac RAAS
Dr Amarpal Singh Gulati
Asst. Prof. Dept. of Cardiology
Nizam’s Institute of medical Sciences

2. Definition
“The renin-angiotensin system (RAS) is a
peptidergic system with endocrine
characteristics.”

3. How the RAAS Was Seen
in the Past
•Substrate : Angiotensinogen, an α-glycoprotein,
released from the liver
•In the circulation, enzyme renin, secreted from theII “main effector”
Circulating Ang
juxtaglomerular apparatus of the kidney forms the
decapeptide angiotensin (ANG) I.
Involved in
•global regulation of sympathetic
•ANG I is then activated to the octapeptide ANG II by
angiotensin converting enzyme (ACE), a activity
•Regulation of blood pressure
membrane-bound metalloproteinase, which is
•Fluid and electrolyte balance
predominantly expressed in high concentrations on
the surface of endothelial cells in the pulmonary
circulation.
•ANG II, considered the main effector peptide of the
RAS, which acts on specific receptors on vascular
smooth muscle cells to induce vasoconstriction or,
by stimulating the release of aldosterone from the
adrenal cortex.
Vascular Disease Prevention, 2009, 6, 65-74

4. POSITIVE FEEDBACK EXISTS BETWEEN DISEASE PROCESSES IN THE
CARDIORENAL CONTINUUM
HTN RAAS activity
Ang II
Oxidative stress/
Vasoconstriction
IGT
DM risk
CVD risk GFR
SCr
Glomerular
pressure
•Atherosclerosis
•cardiac hypertrophy
•fibrosis, Glomerular
sclerosis
MAU
UAER •nephropathy of diabetic
and nondiabetic etiology.
Macro- CKD
albuminuria
proteinuria
Predicts stroke,
Technical Advances
ESRD
CHD, CVD risk 1. molecular biology
CHD=coronary heart disease; IGT=impaired glucose tolerance; UAER=urinary albumin excretion rate rat
2. Availability of transgenic and knock-out models
CHD=coronary heart disease; IGT=impaired glucose tolerance; UAER=urinary albumin excretion rate
with altered expression of RAS components.
Kopyt NP. JAOA. 2005;105:207–15.
4
Kopyt NP. JAOA. 2005;105:207–15.

5. • Circulating Ang II levels tend to increase in
patients taking ACE inhibitors over long
periods.
• “ACE is not the only enzyme implicated in the
generation of Ang II”

6. Interplay of recently discovered components of
the renin – angiotensin – aldosterone system.
Alternative pathways of ANG
II formation
Concept of “local” or
“tissue” renin
angiotensin systems
Additional truncated
peptides
(1-9) & (1-7)
Different ANG receptors and
signal transduction
pathways
European Heart Journal (2011) 32, 2739–2747

7. •Prorenin can be activated by
•Proteolytic :Endopeptidases/trypsin/cathepsin B or
•Nonproteolytic :low pH
• Three receptors
•Mannose-6-phosphate receptor (M6P)
•Endothelial cells
•Clearance mechanism
•Prorenin binding protein
•Cardiac cells
•Local tissue RAAS
•45-kDa membrane protein binding both prorenin and
renin
•Angiotensin independent effects
•Cofactor in increase production of Ang I
•Activation of
•promyelocytic zinc finger (PLZF)
•protein-phosphatidylinositol-3-kinase
•mitogen-activated protein kinases
(MAPKs)
•localized in the mesangium (kidney) and in the
subendothelium of renal, uterine, and cardiac
blood vessels

8. Newer Theraupeutic Targets
“1” •Direct renin inhibitors
DRI’s •like aliskiren
•attenuate the plasma renin activity which is
increased by ACE inhibition or AT1R blockade
•High renin levels cause ‘escape’ from renin inhibition
•Do not prevent binding of renin to the (P)RR.
•A handling region peptide (HRP) inhibiting the binding of
prorenin to (P)RR,
•completely abolished diabetic nephropathy in AT1R knockout mice
“2” •Reduced cardiac fibrosis in stroke-prone Spontaneously
Angiotensin
Hypertensive Rats
Independent •reduced cardiac hypertrophy and fibrosis
Effects
•HRP were only effective in low-renin conditions
Ichihara A et al. Hypert ens Res 2010;33:177 – 180
Susic D et al. Am J Physiol Heart Circ Physiol 2008;295:H1117 – H1121.

9. cleavage of the COOH-terminal dipeptide
Angiotensin converting enzyme ACE independent enzyme activity
• chymases,
• In circulation – high substrate specificity
– Cellular localization largely restricted to
mast cells
– Normally remains inactivated
• Locally expressed – Selective chymase inhibitors used in
animal models
•Mediate > 80% of AngII formation in
• carboxypeptidases,
the heart and >60% in the vessels
• cathepsin G
•Not inhibited by ACE inhibitors
• tonin.
•Upregulation during pathologic
conditions causing increased local Ang
• neprylisin II generation
•Also form Alternative cleavage
products

10. White bars : nondiabetic controls
(control)
Black bars : streptozotocin (STZ)-
induced diabetic hamsters (STZ)
Hatched bars : STZ hamsters rendered
normoglycemic by continuous
intraperitoneal insulin infusion (STZ
CIPII).
Quantification of hamster chymase and ACE mRNA in the kidney by real-time PCR.
Results are shown as a percentage of controls.

11. ACE (dipeptidyl-carboxypeptidase) subtypes
• Two distinct forms of ACE • Two active sites
– Somatic form on the endothelial – N-terminal domain
cells(lung, smooth muscle cells, • Ang 1-7 cleavage
monocytes, T lymphocytes, and – C-terminal domain
adipocytes) • Responsible for Ang I conversion
– Germinal form (testis) • Selective C domain inhibition is
• glycosylphosphatidylinositol (GPI) sufficient to prevent Ang I–induced
hydrolase activity not inhibited by ACE vasoconstriction
inhibitors • Both sites required for degradation of
• capacitation, formation of the sperm bradykinin
membrane, located on the
1. endothelium
of all blood vessels
• Two types of Existence 2. In the
parenchyma of the
– At the cell surface (ectoenzymes) heart, kidneys,
brain, and adrenal
hydrolyzing circulating peptides glands.
2. Also in non-
– Soluble form (plasma ACE) after action endothelial cells
such as
of ACE secretase macrophage
• lungs have traditionally been
considered to be an integral part of the
circulating RAS
• 10% of total ACE
• Risk factor for coronary stent restenosis,
CAD, MI and post MI LV dilation Anchored to the plasma
membrane

12. “Local” or “tissue” renin angiotensin systems
• RAS components in “unlikely” places
– such as the “kidney enzyme” renin in the brain
– Local expression of angiotensinogen, renin, renin-binding protein, ACE,
chymase, as well as Ang II receptors and secretion of Ang II.
• “Tissue-based synthesis of ANG II”
– Angiotensin and renin messenger RNA (mRNA) has been discovered in
12 different extrahepatic tissues of rats, strongly suggesting that there
is local synthesis of angiotensinogen and renin
• Local synthesis or Uptake from the circulation
• Clinical relevance : “Dissociating from the class effect”

13. • Both Local and systemic actions of the RAS integrate and cause ANG-
mediated effects
Though
• An independent function of local RAS (for example, in the brain, inside the
blood-brain barrier as well as in testis/ovary/bonemarrow and so on)
• Local RAAS at the cellular level
– Paracrine
– Autocrine effects
• cell growth, proliferation, and metabolism
– Intracellular or intracrine RAS sffects
• ANG binding in the cell nucleus

14. The renin-angiotensin system
(RAS) in the heart.
•Contractility
•Chronotropy
•Hypertrophy
•Apoptosis
•Fibrosis
Inducers of ACE
1. Vol or press overload
2. Wall stress
3. CHF
4. MI
5. aging
endothelium
Physiol Rev • VOL 86 • JULY 2006

15. •Van Kats et al. used infusions of radiolabeled ANG I and ANG II peptides in pigs and
measured plasma and tissue levels of endogenous as well as the radiolabeled
peptides.
•>90% of cardiac ANG I is synthesized locally in the heart
•>75% of cardiac ANG II is synthesized locally, most of it using local ANG I generation
as a basis.
•Concept of a cardiacClinically,dependent only on the extremely of
1) RAS is not ACE inhibitors are local synthesis
angiotensinogen and renin. in the treatment of cardiac disease;
efficient
ACE independent pathways
•Tissue ACE is regarded as the vital rate limiting enzyme in the local elaboration of
AII 2) Most of the ANG II generatedin intact cardiac
are particularly important
by
disease states such as cardiac
blood vessels can heartblocked by ACE
hypertrophy and be failure
inhibitors;
•. Even partial inhibition of cardiac ACE has been shown to contribute to the
e.g,
beneficial effects associatedACE expression is higher in
with ACE inhibitors in patients with heart failure,
hypertension, or coronary artery disease as well as in
ruptured plaque
3) Expression of human heart chymase is highly
the macrophages around
compartmentalized and mostly restricted to
ruptured plaque
mast cells

16. Activation of a local renin-angiotensin system (RAS) in heart
IPC
•~50,000 mast cells/g human
heart tissue in close proximity
to vessels and nerves
• Density further increases in
heart failure, ischemic
cardiomyopathy and
experimental infarct models
Circulation. 2010 August 24; 122(8): 771–781

17. RAS after LVAD
European Heart Journal (2009) 30, 805–812

18. Local RASS in Kidney
Proximal tubular cell
1. Unlike heart Ang II is required
for normal renal development
2. Activated by
•Hyperglycemia
•Proteinuria
•Renal injury
•Reduction in calcitriol
3. ACEI’s do not significantly
reduce intrarenal AngII
production which is regionally
4. Never the less, antihypertensive therapy with compart-mentalized and in
ACE inhibitors, successfully ameliorates proteinuria endosomes
suggesting beneficial effects independent of
reductions in blood pressure.
5. Also decreases risk associated with death,
dialysis, increased creatinine, and transplantation Wolf G et al. Nephron Physiol 93: 3–13, 2003

20. Tissue ACE and the Vasculature
• Endothelial cells cover 700 m2 and weigh 1 • Locally produced AII is responsible for
to 1.5 kg in a 70-kg individual endothelial dysfunction.
• Vascular homeostasis • Local renin production as well as
– relaxation and contraction; endothelial ACE upregulation occurs in
– thrombogenesis and fibrinolysis; response to injury
– platelet activation and inhibition; – Hypercholesterolemia,
– Cellular growth stimulation and inhibition. – smoking,
– hypertension,
• The vascular wall is the effector organ for the – aging,
hormonal or plasma RAS – Diabetes
• The substrate mRNA levels are abundantly • Expression of ACE is further modulated
expressed in periadventitial fat cells by
– steroids,
– calcium ionophores,
• Renin uptake also takes place via unspecified – growth factors
binding sites on endothelial cells or specific
prorenin/renin receptors
– Clearance mechanism as well as pathological

21. Tissue ACE and Endothelial
Dysfunction
• Ang II ↑ NADPH+, producing superoxide anion
and hydrogen peroxide that inactivate NO
The reduction of tissue AngII
• Oxidative stress also activates the transcription
of factor NF-κ B that induces the expression of increased
and NO
bioavailability may underlie
genes controlling cytokine formation and
leukocyte adhesion to the vessel wall
the mechanisms by which
• ACE degrades and inactivates bradykinin, inhibitors exert their
ACE hence
vasoconstriction and inflammation vasculoprotective effects.
– ↓ NO and other endothelial derived vasodilators
– ↑ vascular smooth muscle cell growth and
migration
– ↑ expression of VCAM-1 & monocyte
chemoattractant protein-1
– ↓ plasminogen activator
• AngII also stimulates the production of
endothelin-1 (potent vasoconstrictor) and
plasminogen activator inhibitor-1 (PAI-1)

22. Balloon angioplasty induced
endothelial dysfunction
• Percutaneous transluminal coronary angioplasty (PTCA) injury in
humans results in upregulation of ACE at sites of active repair
• After pretreatment with perindopril, there was a reduced
neointima formation after balloon injury of rabbit carotid artery
• Trial on Reversing Endothelial Dysfunction (TREND)
– CAD patients
• normotensive,
• had no heart failure, Free of RAS activation
• no major lipid abnormalities;
– randomized to placebo or quinapril and followed for 6 months
– quinapril experienced significant improvement in endothelial
response over those patients who had received placebo ( P = 0. 002).
Ohishi M et al.Circulation 96: 3328 –3337, 1997
Circulation 1996;94:258–265.

23. RAAS: BENEFICIAL EFFECTS OF INHIBITION
ON THE CVS AND KIDNEY
Cardiovascular system (CVS) Kidney
• ↓ Elevated BP • ↓ Sodium and water reabsorption
• ↓ Vascular smooth muscle cell • ↓ Proteinuria
growth • ↓ Glomerular and tubulointerstitial fibrosis
• ↓ LVH • Stabilization of renal function in CKD
• Prevents LV remodeling after MI
• Prevents HF after MI
• ↓ Sympathetic NS activity
• Stabilization of atherosclerotic plaque
• Normalization of endothelial function
• ↑ Fibrinolytic system
LVH=left ventricular hypertrophy; NS=nervous system
Cowie MR. In Cardiovascular Medicine. Eds: Willerson JT, et al. 2007.

24. Other organs/systems
• Skin
• Digestive organs
• Sensory organs
• Lymphatic tissue
• Bone marrow
• Adipose tissue

26. RAS in the brain.

27. RAS in the ovary

28. RAS in the testis and epididymis

29. Pharmokinetics of Angiotensin-Converting
Enzyme Inhibitors
• 2-methylpropranolol-L-proline moiety is common (active
site)
• Functional group :Adherence to the zinc component of the
active site of ACE (potency dependent on strength of
binding) quinaprilat =benazeprilat >
1. carboxyl-containing ramiprilat > perindoprilat >
2. Sulphydryl containing lisino-pril > enalaprilat >
fosinoprilat > captopril
3. phosphoryl-containing
• Drug lipophilicity
– tissue penetration
– differences in clinical effect ?
Clin. Cardiol. Vol. 28, December 2005

30. Issues
• Lipophilicity (α ACEI activity) • Tolerability
• Potency • Prodrugs
• Bioavailability •Hemodynamic effects: well proven as in trials of
• Plasma levels
CHF/MI
• bradykinin selectivity and potentiation • intermediary metabolism
• effects on endothelial-cell apoptosis •Local vasculoprotective effects: CAD /
• half-lives
endothelial dysfunction, validated 1st by HOPE
• Co-morbidity • Elimination
• Evidence based • durations of action OR
• trough:peak plasma concentration relationships
•Peripheral drug effects e.g decreasing afterload
• Design
•CardiacDemographics as in CHF (as seen in aorta
• drug effects
clipped model )
• Prostaglandins & free radicle scavanger

31. Major morbidity – mortality studies of angiotensin-converting
enzyme inhibitors across the continuum of cardiovascular disease

32. Relative tissue affinity of various angiotensin-converting
enzyme inhibitors
Relative selectivity of angiotensin-converting
enzyme (ACE) inhibitors for bradykinin vs.
Ferrari R et al.Dialogues Cardiovasc Med 2004; 9 :71 –89
Ceconi C et al.Eur J Pharmaco l 2007; 577 :1– 6. angiotensin I binding sites on ACE

33. Effects of ACE Inhibitor administration on Decreasing lipopolysaccharide
(LPS)-induced endothelial apoptosis in rat aorta
Ceconi C et al.Cardiovasc Drugs Ther 2007; 21 :423 – 429.

34. •↓LDL
BANFF
•Statins
•High-resolution usg used for brachial art flow mediated
vasodilation (FMD) before & after 8 wks of treatment. Quinapril is known to decrease vol overload
•relatively lower-
hypertrophy compared to enalapril
•CAD pts had impaired FMD compared to pts without CAD. risk pt population.
•Among the antihypertensive agents tested (quinapril, enalapril,
losartan, amlodipine), only quinapril significantly Circulation 1995;91:16–19.
improved FMD .
Am J Physiol 1997;273:H641–H646
J Am Coll Cardiol 2000;35:60–66.78].
•Quinapril Ische-mic Event Trial (QUIET)
•CAD without left ventricular dysfunction
•quinapril failed to reduce cardiovascular events overall
•Subset with increased concentration of LDL cholesterol improvement seen.
•High tissue affinity alone cannot determine the effectiveness of an ACE inhibitor in preventing cardiovascular events
though it is an important component
•Other pharmacologic and structural characteristics of ACE inhibitors result in differences in effectiveness.
•Perindopril or ramipril is likely to be a better therapeutic option than certain other ACE inhibitors in the setting of
stable CAD.

35. RAAS Blockade with ARB;
ACEI and ARB : Is there difference?
Ang II Ang II
The Blood Pressure Lowering Treatment Trialists’ Collaboration—
•meta-regression analyses of 26 large-scale trials
AT1 AT2
•Almost 150 000 patients with hypertension or ↑ CVD risk
X
•ACE inhibitors and ARBs produced Bradykinin
similar BP-dependent decreases in
NOS
the risks of major coronary heart disease (CHD) events, such as stroke
and heart failure NO
•However, ACE inhibitors, but not ARBs, had effects beyond BP lowering
cGMP
•(9%) of ACE inhibitor efficacy in reducing CHD risk was attributed to
Proliferation
BP-independent effects( P =0.002)
Antiproliferation Vasodilation
Vasoconstriction
J Hype rtens 2007; 25 :951 –958.

36. Angiotensin 1 -9 (Ang1-9) & Ang1-7
• Ang 1-9
– reduces AngII
– increases Ang1-7 levels ACE 2
– Stimulates bradykinin
release •Novel enzyme similar to ACE, called angiotensin-
converting enzyme 2 (ACE2)
– Directly binds the AT 2R
•Removes the COOH-terminal amino acid phenylalanine
and has 400-fold less affinity to Ang I than to Ang II
• Ang1-7 blocks the des-Arg(9)-bradykinin
•ACE2 can cleave
effects of AngII via the
G protein-coupledACE inhibitors
•Insensitive to
receptor Mas

37. •AT2R •Mas
•Inhibits MAPKs, activates •Promotes Akt
NO/cGMP and phospho- phosphorylation,NO
lipase A2 pathways release.
•Stimulation with a
•Stimulation with non-
synthetic peptide
peptide agonist,
induced vasorelaxation,
compound 21, improved
reduced BP in
myocardial function in
spontaneously
rats with myocardial
hypertensive rats (SHR)
infarction independently
and showed
of BP effects, along with
anti-inflammatory action antiarrhythmic effects.
and NF-k B inhibition
Funke-Kaiser H et al. J Renin Angiotensin Aldosterone Syst 2010;11:7 – 17
Savergnini SQ et al.Hyp ertension 2010;56:112 – 120

38. Cardiac ACE2/Ang-(1–7)/Mas Axis
• Protective role of ACE2 in the heart
• Vascular endothelial cells( including kidney, lung & small
intestine), cardiomyocytes, fibroblasts & myofibroblasts
• ACEi, ARBs, and aldosterone receptor blockers, increase ACE2
activity/ expression Ang II
• Ang-(1–7) causes vasodilation in forearm circulation of
normotensive subjects and patients with essential
hypertension but no significant effect in the same vascular
territory in ACEi-treated patients
• Activation of Endogenous ACE2 (XNT) causes a dose-dependent
hypotensive effect in normotensive and hypertensive rats but
no significant effect in response to the administration of Ang II
or Losartan
With XNT
Without XNT
International Journal of Hypertension
Volume 2012 (2012), Article ID 147825, 13 pages
doi:10.1155/2012/147825

39. Metabolism of bradykinin [BK-1-9]
Kinins
•Vasodilators
•Promote diuresis
Removal of two C-
•Natriuresis
terminal dipeptides •Cardioprotective actions
•Prevention of cardiac hypertrophy
•Reduction in infarct size
•Regulate coronary vascular tone and BP
•Contribute to the vasodilation in heart failure
•Doppler imaging used to measure radial artery blood
•Captopril + bradykinin receptor antagonist HOE140 •High levelsflowkinin peptides produce
of effects of
•high tissue-affinity ACE inhibitor (quinaprilat)
given to both normotensive and hypertensive subjects •inflammation
•HOE140,
•HOE140
•Angioedema •Combination.
•reduced the hypotensive effect of captopril,
•Quinaprilat increased flow nearly 50% over baseline,
Contribute/Support/Mediate
•renal hemodynamic response to captopril was not
changed, the cardiac effects of ACEI
•HOE140 decreased flow from baseline by 33%.
•response of plasma renin activity to captopril was
significantly altered
•Coadministration yielded results similar to those
N Engl J Med 1998;339:1285–1292. obtained with the B2 antagonist alone
Hypertension. 2003;41:383-389
Circulation 1997;95:1115–1118.

40. ACE & NEP
• ACE and NEP are 2 membrane-bound zinc-
containing metallopeptidases involved in the
ACE NEP
metabolism of a variety of biological peptides
Angiotensin (Ang) I Natriuretic peptides.
Ang-(1-7) Ang I
Kinin peptides bradykinin Ang II
• Tissue distribution
and kallidin
– The vascular endothelium Kinin peptides
Chemotactic peptide
– smooth muscle cells
Enkephalins Substance P
– cardiac myocytes
Neurotensin Adrenomedullin
– fibroblasts, P
Substance Endothelin
– Brush border of proximal tubule cells of the kidney,
LH–releasing hormone Chemotactic peptide
– BrainHemoregulatory peptide N- Enkephalins, and the Amyloid
acetyl-Ser-Asp-Lys-Pro peptide.
Erdos Eget al. FASEB J. 1989;3:145–151.
Ferrario CM et al.Hypertension. 1997;30:535–541.

41. Effects of ACE Inhibition
ACE
Independent
pathways
↑Renin
Hypertension. 2003;41:383-389.

42. Vasopeptidase Inhibitors: Dual ACE/NEP
Inhibition by a Single Molecule
OCTAVE
IMPRESS
OVERTURE
•Major concerns were
•Angioedema
•upto 4 times
•Particularly in HTN rather in HF
•More of ACE inhibition rather than NEP
inhibition

43. •Angiotensin type 1
receptor (AT1R)
•mediates most of the
Ang II effects
Lower Affinity
•Trigerrs aldosterone
release
•Telmisartan or losartan
with its metabolite XP
3179, might offer even
more metabolic
protection as they have
peroxisome proliferator-
activated receptor-γ
activating properties.
•AT4R : predominantly in
kidney (endothelial cells
and tubules)
Kappert K et al.Hypertension 2009;54:738 – 743.
J Physiol 589.4 (2011) pp 939–951

44. Aldosterone receptor antagonists
• Aldosterone is generated in many tissues besides the
adrenal cortex and is involved in endothelial dysfunction,
inflammation, proteinuria, and fibrosis
•Blockade of mineralocorticoid receptors presumably is
beneficial even in situations with high AngII, because of
common signal transduction pathways
Spironolactone
Eplerenone
•Reduce BP (Resistant hypertension)
•Selective for MR
•Diminish urine protein excretion
•200 mg b.i.d. required to achieve BP
•Confer CV gain in heart failure apparently
reduction comparable with 50 mg
independently of volume alterations
spironolactone b.i.d.
•Reduces the apnoea-hypopnea index in patients
with OSA
Nishizaka MK et al. Am J Hypertens 2003;16:925 – 930.
Sica DA et al. J Clin Hypertens (Greenwich) 2011;13:65 – 69.

45. Non-steroid generation of MRAs .
Nimodipine
WO2005097118;
DE102005034267
Dietz JD et al. Hyp ertension 2008;51:742 – 748.
Arhancet GB et al. J Med Chem 2010;53:4300 – 4304.

46. Aldosterone synthase inhibitors
•Fadrozole
• Aromatase inhibitor or its dextroenantiomer
(FAD286)
•Reduces mortality, cardiac hypertrophy,
albuminuria, cell infiltration, and matrix
deposition in the kidney in double transgenic
renin rats (dTGR)
•Both FAD286 and MRAs comparably reduced
hypertrophy and interstitial fibrosis of the kidney
and heart induced by Ang II and a high-salt intake
•No profound effect on BP
•LCI699
•Reduced 24 h-ambulatory systolic BP by - 4.1
mmHg after 4 weeks of treatment
•Suppressed supine plasma aldosterone
concentrations
•ACTH concentrations were also elevated though
cortisol remained same
Fiebeler A et al. Circulation 2005;111:3087 – 3094.
Amar L etal.Hyperte nsion 2010;56:831 – 838

47. Cross-talk between statin and RAAS
Cross-talk between PPARs and RAAS
•Hypercholesterolemia is
associated with AT1-receptor
upregulation and increased O2-
production secondary to an
activation of vascular NADPH
oxidase.
•Pioglitazone inhibits gp91phox
expression, and attenuatsed toxic
peroxynitrite (ONOO-) formation
•Statins, thiazolidinediones (PPARγ agonists) and RAAS blockade may have additive
beneficial effects on endothelial function, insulin resistance, and atherosclerosis
•Telmisartan and losartan also have additional inbuilt PPARγ agonist activity
Koh KK et al. Int J Cardiol 2009;132:297–9. [PubMed: 19136168]
Vascular Disease Prevention, 2009, 6, 65-74

48. Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline)
• The breakdown of Ac-SDKP can be blocked by ACE inhibitor
treatment resulting in an increase of its plasma levels
• Measurement of Ac-SDKP could be a marker for the clinical
efficiency of ACE inhibition
• N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), is a hematopoetic
factor (acts on the cell cycle and prevents the activation of
pluripotent stem cells)
• Increased levels of Ac-SDKP have recently been associated
with anemia in heart failure patients treated with ACE
inhibitors
Van der Meer P et al.Circulation 112: 1743–1747, 2005.

49. ACE Inhibitor and ARB Effects
“Independent of the RAAS”
• ACE inhibitors as well as AT1 receptor blockers can
influence cellular functions independent of inhibition
of the RAAS.
– ACE inhibitors block the hydrolysis of Ac-SDKP
• Hence inhibition of fibrosis, reduction of inflammatory cell
infiltration
– Ramiprilat and perindoprilat increase CK2-mediated
phosphorylation of serine1270 and increase the activity of
N-terminal kinase in endothelial cells (↑NO)
• Hence mediate cellular function by “outside-in” signaling directly
through ACE
– The PPAR-γ activating properties of certain sartanes
(molecular structure of the specific sartanes)
Peng H et al. Circulation 112: 2436 –2445, 2005
Fleming I et al. Curr Opin Neph-rol Hypertens 15: 8 –13, 2006

50. Conclusion
• With overexpression of RAS components or
inhibition of others, the RAS becomes a
mediator of pathophysiological stimuli:
– Most importantly “progression of atherosclerosis
in multiple organs”
• The search for new members/components /
pathways still continues.
• It offers new and promising drug targets

51. Conclusion
• The concept of tissue RAS, should not be considered as
an opposing or alternative but rather as a
complimentary or integrated functional concept of
ANG formation and function.
• The plasma RAS : Acute “response unit”
• Tissue RAS : Subacute and chronic modulation
• Tissue ACE inhibition results in vasculoprotection
beyond blood pressure reduction alone

52. “There is clearly no basis for any controversy”
THANK YOU