Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 12, 2007
Contents
Part-I
Applications of Angiotensin Converting Enzyme Inhibitors
and of Angiotensin II
Receptor Blockers in Pharmacology and Therapy: An Update
Executive Editor: Agostino Molteni
Editorial: Pp. 1187-1190
Demystifying the ACE Polymorphism: From Genetics
to Biology Pp. 1191-1198
R. Castellon and H.K. Hamdi
[Abstract]
Pharmacological, Immunological, and Gene Targeting
of the Renin-Angiotensin System for Treatment of Cardiovascular
Disease Pp. 1199-1214
R. Igic and R. Behnia
[Abstract]
The Renin Angiotensin System in the Regulation of
Angiogenesis Pp. 1215-1229
S.C. Heffelfinger
[Abstract]
The Two fACEs of the Tissue Renin-Angiotensin Systems:
Implications in Cardiovascular Diseases Pp. 1231-1245
E. Lazartigues and J.L. Lavoie
[Abstract]
Angiotensin-TGF-β1
Crosstalk in Human Idiopathic Pulmonary Fibrosis: Autocrine
Mechanism in Myofibroblasts and Macrophages Pp. 1247-1256
B.D. Uhal, Y.K. Kim, X. Li and M. Molina-Molina
[Abstract]
Attenuation of Bleomycin-Induced Pulmonary Fibrosis
by Intratracheal Administration of Antisense Oligonucleotides
Against Angiotensinogen mRNA Pp. 1257-1268
X. Li, J. Zhuang, H. Rayford, H. Zhang, R. Shu and B.D.
Uhal
[Abstract]
General Articles
The Neurobiological Bases for the Pharmacotherapy of Nicotine
Addiction Pp. 1269-1284
V. Di Matteo, M. Pierucci, G. Di Giovanni, A. Benigno
and E. Esposito
[Abstract]
The Protease of Human T-Cell Leukemia Virus Type-1
is a Potential Therapeutic Target Pp. 1285-1294
J. Tözsér and I.T. Weber
[Abstract]
Abstracts
[Back to top]
Editorial: Applications of Angiotensin
Converting Enzyme Inhibitors and of Angiotensin II
Receptor Blockers in Pharmacology and Therapy: An Update
About three years ago we discussed in this Journal the
development of additional potential applications of angiotensin
converting enzyme inhibitors and of Angiotensin II (ANG II)
receptor blockers in therapy. The deployment of these drugs
in the treatment of diverse vascular conditions has been,
for many years, a well established medical practice and every
year millions of individuals benefit from this treatment.
This successful deployment underlines the relevance that the
renin-angiotensin-aldosterone system (RAAS) plays in the regulation
of the control mechanisms of our blood pressure and, more
in general, of our homeostasis. It emerged, however, from
many articles of that publication that the RAAS system and
ANG II in particular, play additional roles in the modulation
of our homeostasis such as the regulation of apoptosis, the
modulation of cellular growth, specifically of fibroblasts
and endothelial cells, and the modulation of angiogenesis.
Additional information has been added in the past two-three
years to these data. More knowledge also became available
about the RAAS system genetic regulation, its interaction
with prostaglandins and with other substances also controlling
blood pressure, and about the presence and physiological role
of another converting enzyme: ACE II. The presence of the
various components of the system at local level in several
tissues has also become relevant, especially their action
on the smooth muscle fibers of the wall of arteries and arterioles
of several organs, kidneys, and lungs in particular, or for
the apoptotic regulation of many tissues.
All these observations open the possibility of the deployment
of ACE inhibitors and of A2 receptors antagonists as pharmacological
modulators of many diseases other than hypertension.
This journal’s issue reviews and revises some of the
previous experiences with these drugs and deals with some
novel applications and deployments of them.
Drs. Hamdi and Castellon [1] discuss the role that ACE polymorphism
plays with a large number of diseases including cardiovascular,
metabolic, immune, cancer, aging, neurodegenerative and psychiatric
disorders and they report and summarize these associations.
These observations lead to the question why this ACE polylmorphism
is associated with so many diseases and what its function
is. In the past, much attention has been given to the role
that ACE, especially somatic ACE, plays on the synthesis of
Angiotensin II in different tissues and on the extensive role
that this octapeptide plays in the general homeostasis regulation.
ACE, however, has been found to convert many other peptides
and the investigation of these functions is extended to test
the association of this polymorphism with the levels of other
ACE isoenzymes. The experience with various ACE isoforms and
their effect on cell’s survival may better explain the
ACE/ID polymorphism associated with many diseases.
Drs. Igic and Behnia [2] report the pharmacological, immunological
and genetic targeting of the Renin-Angiotensin system for
the treatment of cardiovascular diseases. The investigators
present the various components of the Renin Angiotensin system
(RAS), discuss the biological activities of angiotensin peptides
and the role of the enzymes that generate and metabolize the
various types of angiotensin. They devote special attention
to the role of Renin, ACE, ACE 2, chymase and neprylysin.
Subsequently, on the basis of the experience with ACE inhibitors
and type 1 ANG II receptor blockers, they discuss the rationale
to target the RAS in its control of general homeostasis. Finally,
they present the investigational agents acting on the RAS,
which posses a potential for clinical deployment and give
the perspective of pharmacological immunological and genetic
targeting of the RAS for the treatment of cardiovascular diseases.
Dr. Heffelfinger [3] discusses the role of RAS in the regulation
of angiogenesis. It is well established that ANGII and bradykinin
are angiogenic agents and affect the microvascular circulation.
That implies that the ACE inhibition would have an impact
on angiogenesis in vivo depending upon which factors
are present in the system. The author reviews several conditions
such as peripheral ischemia, stroke, retinopathy and cancer
in relation to ANGII and bradykinin activity and evaluates
the impact that ACE inhibitors posses in all those clinical
conditions. It appears that peripheral ischemia and stroke
seem to be dependent for angiogenesis regulation by bradykinin
signaling, while cancer and retinopathy are more dependent
upon ANGII. Published data on in vitro cultures as
well in animal models suggest interesting predictions about
how the RAS and bradykinin may function in humans and many
data are now accumulating in humans confirming the data derived
from experimental work. Modulation of angiogenesis by ACE
inhibitors and ANG II receptor blockers may become a new therapeutical
property of these drugs.
Drs. Lazartigues and Lavoie [4] report about the pathophysiology
of the two fACEs present in various tissues, both being components
of the RAS, and about their implications in cardiovascular
diseases. It is now well established that ACE works not only
by generating ANG II but also by interacting with some receptors
outside the RAS like the receptors for bradykinin. More recently
came the discovery of a new ACE homolog identified as ACE2,
which may play a pivotal role in controlling the balance in
the RAS between the vasoconstrictive effect of ANGII and the
vasodilatatory properties of the Angiotensin 1-7 peptide.
ACE2, like ACE, may also hydrolyze peptides not related with
the RAS and this enzyme has also been identified as a receptor
for the severe acute respiratory distress syndrome (SARS)
induced by coronavirus.
In the article, the authors also compare the structure, distribution
and properties of these two carboxypeptidases in the context
of the cardiovascular function since the heart is the organ
where ACE2 activity has been more widely studied. However,
they not only focus their study on the autocrine-paracrine
heart system, but also evaluate ACE2 role on the brain and
indicate potential therapeutic application of the said enzyme
in the treatment of cerebral disorders.
ANGII has been also identified as a proapoptotic and an antifibrotic
factor both in experimental animal models of lung fibrosis
and in humans presenting the ID/DD polymorphism of ACE which
would confer to those individual’s high production of
the enzyme and, consequently, of ANGII. Moreover, lung fibroblasts
isolated from patients suffering with Idiopathic Pulmonary
Fibrosis (IPF) synthetize constitutionally the ANGII precursor
Angiotensinogen (AGT). Uhal and Co. [5] demonstrated that
cultures of lung fibroblasts of patients with IPF synthetize
large amounts of ANGII and ACT in addition to TGFβ1mRNA
and that those effects are limited when the ANGII receptor
antagonist Saralasin is added to the media. Antisense oligonucleotides
against TGFβ1
mRNA or TGFβ1
neutralizing antibodies, when applied to the fibrotic HIPF
cells in serum free media, significantly reduce AGT expression.
In tissue sections from IPF patient biopsies, immunoreactive
AGT/ANGI proteins were detected in myofibroblasts, epithelial
cells and presumptive alveolar macrophages. According to Uhal
et al, [5] all these data support the existence of
an angiotensin TGFβ1
“autocrine loop” in human lung myofibroblasts
and also suggest ANG peptide expression by epithelia and macrophages
in the IPF lung. These findings may explain the ability of
ACE inhibitors and ANG II receptor antagonists to block experimental
lung fibrosis in animals, and support the need for evaluation
of these agents for potential treatment of human IPF.
Apoptosis of alveolar lung epithelial cells (AECs) is also
believed to be critical for the development of Bleomycin (Bleo)-induced
pulmonary fibrosis. Dr. Li and coll. [6] showed that apoptosis
of alveolar epithelial cells in response to Bleo administration
could be abrogated by antisense oligonucleotides against angotensinogen
(AGT) mRNA In a BLEO-induced rat model of pulmonary fibrosis,
endogenous lung AGT was upregulated in vivo as early
as three hours after BLEO instillation as detected by RT-PCR,
in situ hybridization and immunohistochemical staining.
AGT mRNA and angiotensin peptides were localized in type II
alveolar epithelial cells and also localized with alpha-smooth
muscle actin (α-SMA),
a marker of myofibroblasts. Tagged antisense administered
I.T. was specifically accumulated by the lung relative to
liver and kidney, and localized primarily in the epithelium
of airways and cells within alveolar walls. The intratracheal
AGT antisense reduced BLEO-induced pulmonary fibrosis measured
by lung hydroxyproline assay, decreased lung AGT and active
caspase-3 proteins, and reduced the number of apoptotic epithelial
cells but had no effect on the serum ANG II concentration.
These data are consistent with the hypothesis that lung-derived
AGT and local pulmonary ANG II are required for BLEO-induced
pulmonary fibrosis, and suggest the possibility of antisense-based
manipulation of the local angiotensin system as a potential
treatment of fibrotic lung disease.
Recent studies have shown that, in addition to reducing blood
pressure, ACE inhibitors and A2 receptor blockers also modulate
inflammation, adhesion molecule expression, and fibrosis.
To assess the therapeutic potential of these inhibitory agents
for the treatment of inflammatory heart disease, the drugs
have been tested in experimental models of infectious and
autoimmune myocarditis. This review by Drs. Daniels, Hyland,
and Engman [7] summarizes the results of studies examining
the efficacy of angiotensin converting enzyme inhibitors and
angiotensin receptor antagonists for the treatment of mouse
models of virus-induced and parasite-induced myocarditis,
as well as autoimmune cardiomyopathy. The collective results
strongly support the use of renin-angiotensin modulation for
the treatment of myocarditis. Importantly, this therapeutic
approach seems to down regulate autoimmunity without causing
immune suppression which may enhance the survival of the disease-initiating
infectious agent.
There is also a wide range of variability in the efficacy
of various ACE inhibitors and ATR antagonists in models of
experimental myocarditis. These differences might be attributed
to specific pharmacokinetic properties of the individual agents
or the fact that some of agents may have additional activities
other than ACE inhibition or ATR antagonism. The answers to
these questions are not fully clear and further experimentation
is needed to provide a more thorough understanding of the
mechanistic action of these important and widely-used agents.
Progressive, irreversible fibrosis is on of the most clinically
significant consequences of ionizing radiation on normal tissue.
When applied to lungs, it leads to a complication described
as idiopathic pneumonia syndrome (IPS) and eventually to organ
fibrosis. For its high mortality, the condition precludes
treatment with high doses of radiation. There is widespread
interest to understand the pathogenetic mechanisms of IPS
and to find drugs effective in the prevention of its development.
Molteni et al. [8] report their experience with the
protective effects of L 158,809, (an angiotensin II (ANG II)
receptor blocker), and two angiotensin converting (ACE) inhibitors
in the development of IPS and about the role of transforming
growth factor β
(TGF-β)
and of alpha-actomyosin (α
SMA) in the pathogenesis of radiation induced pulmonary fibrosis
in an experimental model of bone marrow transplant (BMT).
When L 158,809, Captopril and Enalapril were added to the
radiation and cytoxan treatment, a significant amelioration
of the histological damage as well as the over expression
of alpha actomyosin were observed. Lung concentrations of
Hydroxproline, PG2, TXA2 and of TGF-β
and alpha actomyosin, two proteins involved in the pathogenesis
of pulmonary fibrosis were restored to normal values. The
finding that ACE inhibitors or ANG II receptor blockers protect
the lungs from radiation induced pneumonitis and fibrosis
reaffirms the role that ANG II plays in this inflammatory
process and suggests an additional indication of treatment
of this condition, thus opening a new potential pharmacologic
use of these drugs.
This experiment in vivo also confirms the in
vitro data of Uhal and coll. on the role of TGFβ1
and SM actomyosin in the regulation of fibroblasts and macrophages
growth and the antagonistic effect of ACE inhibitors and ANGII
receptor blockers on such growth.
ANG II also plays a role in the development of renal fibrosis.
This is particularly apparent in models of radiation-induced
nephropathy and it is like for the lungs, a severe limiting
factor in the treatment of radiotherapy for patients. Development
of renal fibrosis has emerged as a significant complication
of bone marrow transplantation and of radionuclide therapy.
The ameliorative action of different ACE inhibitors, Captopril,
in particular and of ANGII type 1 and type 2 receptor antagonists
in the treatment of renal fibrosis is well established.
Moulder, and coll. [9] discuss in their article the difference
between mitigation and treatment of radiation-induced nephropathy
which implies that different mechanisms are operating in the
pathogenesis of this process.
First, a high-salt diet is effective in the mitigation of
radiation nephropathy, but deleterious on the treatment of
established disease. Second, AT1 blockage and ACE
inhibition is highly dependent on drug dose in mitigation
of radiation nephropathy, but not so in treatment. Finally,
while AT1 blockage is effective in mitigation of
radiation nephropathy, it does not do so in treatment. The
authors hypothesize that while mitigation of radiation nephropathy
works by suppression of the RAS, treatment of established
radiation nephropathy requires blood pressure control in addition
to (or possibly instead of) RAS suppression.
Monocrotaline (MCT), a pyrrolizidine alkaloid extracted from
the shrub Crotalaria spectabilis induces in the lungs
of many mammalian species severe hypertension and fibrosis.
Previous work with MCT-induced lung disease in rats has shown
that some of the steps to progressive fibrosis can be interrupted
or decreased by intervention with retinoic acid (RA) or with
the angiotensin converting enzyme inhibitor, captopril. The
report by Baybutt et al. [10] emphasizes the pathology
and cytokines present in lungs of rats in the MCT model of
hypertension and fibrosis in animals treated with captopril,
retinoic acid or a combination of both drugs. TGFβ
was depressed at 30 days by MCT, an effect reversed by a combination
of captopril and RA. RA influences production of an important
Th1 cytokine, IFNγ,
and demonstrated the greatest limitation of MCT-induced TNFα.
The MCT-induced lung pathology of vasculitis, interstitial
pneumonia and fibrosis was limited by captopril. Smooth muscle
actin was overexpressed in MCT treated animals receiving RA,
an effect also observed with treatment with both captopril
and RA. No synergistic or antagonistic activity was observed
when the two drugs were administered together. Each of the
drugs exerts different and particular effects on serum and
tissue levels of various cytokines, suggesting that each drug
is efficient at different points of attack in control of lung
fibrosis.
In the past few years many clinical trials testing the efficacy
of ACE inhibitors (ACEI) and of ANG II receptor blockers have
been conducted. Most of these trials were run in patients
suffering either cardiovascular diseases or renal diseases.
An extensive review of these clinical trials is presented
in this issue by Stojiljkovic and Behnia [11].
In patients with heart failure (HF), ACEI have been shown
to reduce overall mortality and mortality from cardiovascular
causes, to increase life expectancy, as well as to preserve
the renal function (CONSENSUS, SAVE, TRACE, AIRE, AIREX, CATS
trials). In addition, in PROGRESS study ACEI substantially
decreased the risk of stroke and transient ischemic attacks
in patients with cerebrovascular disorders. The HOPE and EUROPA
studies confirmed that long term therapy with ACEI provides
significant survival benefit in patients with a broad range
of atherosclerotic cardiovascular diseases. After these large
and well designed clinical studies, ACEI have become standard
therapy for routine secondary prevention in all patients with
cardiovascular diseases, unless contraindicated.
AT1 receptor blockers have been more recently added to the
cardiovascular therapeutic armamentarium. They are believed
to provide additional protection by inhibition of locally
synthesized angiotensin II on the level of AT1 receptor. ELITE
II, ValHeFT and CHARM studies have shown that AT1 receptor
blockers are equally effective as ACEI in reduction of mortality
and morbidity in patients with HF. Importantly, they may be
used together with ACEI, or as alternative treatment in ACEI
intolerant patients.
Renal protection is another important effect of both ACE and
AT1 receptor blockers that has been confirmed in several large
clinical trials. North American Microalbuminemia Study group
and EUCLID group demonstrated significant reduction in progression
of diabetic nephropathy in patients with insulin dependent
diabetes mellitus (IDDM) treated with ACEI. AT1 receptor blockers
are mainly studied in the non-insulin dependent diabetes mellitus
(NIDDM) nephropathy. Four recent clinical trials (IRMA-2,
DETAIL, RENAAL and IDNT) examined the effect of AT1 receptor
blockers in patients with NIDDM nephropathy. These studies
confirmed the beneficial effect of AT1 receptor blockers in
patients with NIDDM nephropathy that was extended beyond the
blood pressure reduction. Ongoing studies (ONTARGET, TRANSCENT
and PROTECTION) should provide us with additional insights
about cardiovascular, renal and other end-organ protective
effects of these therapeutic agents.
Clinical trials were also conducted in veterinary medicine,
especially for the treatment of small animals (canines and
felines). Dr. Lefevre and coll. [12] present and discuss the
veterinary experience with ACE inhibitors. Less information
from trials with ANGII receptor blockers are presently available.
ACE inhibitors currently approved for use in veterinary medicine
are benazepril, enalapril, imidapril and ramipril. They are
all pro-drugs administered by oral route. ACE inhibitors are
generally well tolerated.
Benazepril, enalapril, imidapril and ramipril are approved
for treatment of dogs with chronic heart failure (CHF). The
efficacy of ACE inhibitors has been convincingly demonstrated
in dogs with CHF, especially in those with chronic valvular
disease. In such clinical settings, ACE inhibitors improve
hemodynamics and clinical signs, and increase survival time.
In cats with cardiovascular disease, little information is
available except for reports of some benefit in cats with
hypertrophic cardiomyopathy in two non-controlled investigations.
ACE inhibitors have also a mild or moderate hypotensive effect.
There is also evidence to recommend ACE inhibitors in dogs
and cats with chronic renal failure (CRF). They decrease the
glomerular capillary pressure, have antiproteinuric effects,
tend to delay the progression of CRF and to limit the extent
of renal lesions.
It is presumptuous to suggest that all the new potential developments
and the new therapeutic applications of ACE inhibitors and
ANG II receptor antagonists have been discussed in this journal
issue. The wide variety of applications and the successful
results seen with the deployment of these drugs in the prevention
of fibrotic processes which ensue in many organs as end-point
damage of various injuries and the potential cytostatic properties
observed both on a variety of cultures of cell lines or in
different types of experimentally induced malignancies open
new ways to use these drugs. If the clinical trials which
are currently on course confirm the successful results observed
at the experimental level, a significant improvement will
derive for the treatment of diseases for which present therapies
are currently limited.
Acknowledgements
The editor wishes to thank Ms’s Kathy Rode and Marilyn
Hall for their invaluable help in dealing with the correspondence
with the authors of the various articles and with Bentham
Co., the publisher, in Karachi, Pakistan.
References
[1] Castellon R, Hamdi HK. Demystifying the ACE Polymorphism:
From Genetics to Biology. Curr Pharm Des 2007; 13(12): 1191-1198.
[2] Igic R, Behnia R. Pharmacological, Immunological, and
Gene Targeting of the Renin-Angiotensin System for Treatment
of Cardiovascular Disease. Curr Pharm Des 2007; 13(12): 1199-1214.
[3] Heffelfinger SC. The Renin Angiotensin System in the Regulation
of Angiogenesis. Curr Pharm Des 2007; 13(12): 1215-1229.
[4] Lazartigues E, Lavoie JL. The two fACEs of the Tissue
Renin-Angiotensin Systems: Implications in Cardiovascular
Diseases. Curr Pharm Des 2007; 13(12): 1231-1245.
[5] Uhal BD, Kim YK, Li XP, Molina-Molina M. Angiotensin-TGF-β1
Crosstalk in Human Idiopathic Pulmonary Fibrosis: Autocrine
Mechansism in Myofibroblasts and Macrophages. Curr Pharm Des
2007; 13(12): 1247-1256.
[6] Li X, Zhuang J, Rayford H, Zhang H, Shu R, Uhal B. Attenuation
of Bleomycin-Induced Pulmonary Fibrosis by Intratracheal Administration
of antisense Oligonucleotides against angiotensinogen mRNA.
Curr Pharm Des 2007; 13(12): 1257-1268.
[7] Daniels MD, Hyland KV, Engman DM.Treatment of Experimental
Myocarditis via Modulation of the Renin-Angiotensin
System. Curr Pharm Des 2007; 13(13): 1299-1305.
[8] Molteni A, Wolfe LF, Ward WF, Ts’ao CH, Molteni
LB, Veno P, Fish BL., Taylor JM, Quintanilla N, Moulder JE.
Effect of an Angiotensin II Receptor Blocker and Two Angiotensin
Converting Enzyme Inhibitors on Transforming Growth Factor
β (TGF-β)
and α-Actomyosin
(α
SMA), Important Mediators of Radiation-Induced Pneumopathy
and Lung Fibrosis. Curr Pharm Des 2007; 13(13): 1307-1316.
[9] Moulder JE, Fish BL, Cohen EP. Treatment of Radiation
Nephropathy with ACE Inhibitors and AII Type-1 and Type-2
Receptor Antagonists. Curr Pharm Des 2007; 13(13): 1317-1325.
[10] Baybutt RC, Herndon BL, Umbehr J, Main J, Xue Y, Van
Dillen C, Halder A, Molteni A. Effects on Cytokines and Histology
by Treatment with the ACE Inhibitor Captopril and the Antioxidant
Retinoic Acid in the monocrotaline Model of Experimentally
Induced Lung Fibrosis. Curr Pharm Des 2007; 13(13): 1327-1333.
[11] Stojiljikovic L, Behnia R. Role of Renin Angiotensin
System Inhibitors in Cardiovascular and Renal Protection:
A Lesson from Clinical Trials. Curr Pharm Des 2007; 13(13):
1335-1345.
[12] Lefebvre HP, Brown AA, Chetboul V, King JN, Pouchelon
JL, Toutain PL. Angiotensin Converting Enzyme Inhibitors in
Veterinary Medicine. Curr Pharm Des 2007; 13(13): 1347-1361.
Agostino Molteni
Departments of Pathology and Pharmacology
University of Missouri- Kansas City
School of Medicine, Kansas City
Missouri 64108, USA
Tel: 816-235-5604
Fax: 816-235-5172
E-mail: moltenia@umkc.edu
[Back to top]
Demystifying the ACE Polymorphism: From Genetics
to Biology
R. Castellon and H.K. Hamdi
The angiotensin converting enzyme (ACE) I/D polymorphism
has been one of the most studied genetic systems. It comprises
hundreds of reports and a myriad of disease associations,
including cardiovascular, metabolic, immune, cancer, aging,
neurodegenerative and psychiatric diseases. Despite the wealth
of information on the ACE polymorphism and the well-known
functions of ACE, several questions arise. Why does the ACE
polymorphism associate with so many diseases? What is its
function? In this review, we summarize the current information
on the ACE polymorphism and explain its function in the context
of cell survival. We also provide a model to understand its
role in biology and disease at the organism and population
levels.
[Back to top]
Pharmacological, Immunological, and Gene Targeting
of the Renin-Angiotensin System for Treatment of Cardiovascular
Disease
R. Igic and R. Behnia
Effective blood pressure control with a large arsenal of conventional
antihypertensive drugs, such as diuretics, beta-adrenergic
blockers, and calcium channel blockers, significantly reduce
the morbidity and mortality associated with cardiovascular
disease. However, blood pressure control with these drugs
does not reduce cardiovascular disease risks to the levels
in normotensive persons. Only two drug classes that inhibit
or antagonize portions of the renin-angiotensin system (RAS),
angiotensin converting enzyme (ACE) inhibitors and angiotensin
receptor type-1 (AT1 receptor) blockers, have protective
and beneficial effects unrelated to the degree of blood pressure
reduction. These drugs may prevent the blood pressure related
functional and structural abnormalities of the cardiovascular
system and reduce the end organ-damage. The first part of
this review presents the components of the RAS, biological
actions of angiotensin peptides, and the functions of the
enzymes that generate and metabolize angiotensins, including
the likely effect of manipulating them. Special attention
is devoted to renin, ACE, ACE2, chymase, and neprilysin. The
second part of this review presents the rationale for targeting
the RAS, based on clinical studies of the ACE inhibitors and
AT1 receptor blockers. Finally, we present the
investigational agents acting on the RAS that have a potential
for clinical usage, and give the perspective of pharmacological,
immunological and gene targeting of the RAS for treatment
of cardiovascular disease.
[Back to top]
The Renin Angiotensin System in the Regulation of
Angiogenesis
S.C. Heffelfinger
Decades of experimentation on angiotensin and bradykinin have
focused on macrovascular systemic effects. However, angiotensin
II and bradykinin are both angiogenic agents, highlighting
their ability to also effect the microvascular circulation.
Not surprisingly, inhibition of angiotensin converting enzyme,
which inhibits angiotensin II synthesis and bradykinin degradation,
would have different impacts on angiogenesis in vivo
dependent upon what factors were present in the system. Several
pathological states in which angiogenesis is important, including
peripheral ischemia, stroke, retinopathy, and cancer are examined
in this review with respect to activity of angiotensin II
and bradykinin and the impact of angiotensin converting enzyme
inhibition. Although generalizations are not without legitimate
criticism, one can think about peripheral ischemia and stroke
as being more dependent upon bradykinin signaling and retinopathy
and cancer as more dependent upon angiotensin II signaling
to drive angiogenesis. Many exceptions are found that are
specific to individual animal model systems. Furthermore,
cancer systems that have been examined at any depth are few.
However, published data on in vitro cultures and
animal models present interesting predictions about how the
renin angiotensin and bradykinin systems may function in humans.
Since angiotensin converting enzyme inhibitors have been widely
utilized pharmaceuticals for many years, we are now accumulating
epidemiological data that test our predictions. The importance
of understanding which agent, angiotensin and/or bradykinin,
appears to be the more important regulator of angiogenesis
in a given pathology will become increasing evident as more
specific angiotensin II and bradykinin receptor blocking drugs
make their way into clinical use.
[Back to top]
The Two fACEs of the Tissue Renin-Angiotensin Systems:
Implications in Cardiovascular Diseases
E. Lazartigues and J.L. Lavoie
The implication of the renin-angiotensin system (RAS) in the
regulation of the cardiovascular system has been well known
for many years. Accordingly, many pharmaceutical inhibitors
have been developed to treat several pathologies, like hypertension
and heart failure, and angiotensin converting enzyme (ACE)
became one of the major target in the treatment of these cardiovascular
diseases. In the last decade however, it has become apparent
that the classical view of the RAS was not quite accurate.
For instance, ACE has been shown to work not only by generating
angiotensin-II but also by interacting with receptors outside
the renin-angiotensin system. Moreover, it has been shown
that many local RAS are present in different tissues, such
as the heart, brain, kidney and vasculature. However, in the
past, it was impossible to determine the role of these local
systems as they were pharmacologically indistinguishable from
the systemic RAS. Hence, in recent years, the development
of transgenic animals has allowed us to determine that these
local systems are implicated in the roles that had been originally
attributed exclusively to the systemic action of the RAS.
However, with almost 30% of the medicated hypertensive patients
harboring an uncontrolled blood pressure, a need for new drugs
and new targets appears necessary. With the new century came
the discovery of a new homolog of ACE, called ACE2, and early
studies suggest that it may play a pivotal role in the RAS
by controlling the balance between the vasoconstrictor effects
of angiotensin-II and the vasodilatory properties of the angiotensin1-7
peptide. Like ACE, ACE2 appears to hydrolyze peptides not
related with the RAS and the enzyme has also been identified
as a receptor for the severe acute respiratory syndrome (SARS)
coronavirus. Although the tissue localization of ACE2 was
originally though to be very restricted, new studies have
emerged showing a more widespread distribution. Therefore,
the whole dynamics of the RAS has to be re-evaluated in light
of this new information.
In this review, we will compare the structures, distributions
and properties of ACE and its new homologue in the context
of cardiovascular function, focusing on the autocrine/paracrine
cardiac and brain renin-angiotensin systems and we will present
recent data from the literature and our laboratory offering
a new perspective on this potential target for the treatment
of cardiovascular diseases.
[Back to top]
Angiotensin-TGF-β1
Crosstalk in Human Idiopathic Pulmonary Fibrosis: Autocrine
Mechanism in Myofibroblasts and Macrophages
B.D. Uhal, Y.K. Kim, X. Li and M. Molina-Molina
Angiotensin II (ANGII) has been identified as a proapoptotic
and profibrotic factor in experimental lung fibrosis models,
and patients with the ID/DD polymorphism of ANG converting
enzyme (ACE), which confers higher levels of ACE, are predisposed
to lung fibrosis (Hum. Pathol. 32:521-528, 2001). Previous
work from this laboratory has shown that human lung myofibroblasts
isolated from patients with Idiopathic Pulmonary Fibrosis
(IPF) synthesize the ANGII precursor angiotensinogen (AGT)
constitutively. In attempts to understand the mechanisms and
consequences of constitutive AGT synthesis by myofibroblasts,
we studied myofibroblast-rich primary cultures of lung fibroblasts
from patients with IPF (HIPF isolates), primary fibroblasts
from normal human lung (NLFs), the IMR90 and WI38 human lung
fibroblasts cell lines, and paraffin sections of lung biopsies
from patients with IPF. Compared to the normal NLF isolates,
HIPF primary fibroblast isolates constitutively synthesized
more AGT and TGF-β1
mRNA, and released more AGT protein, ANGII and active TGF-β1
protein into serum-free conditioned media (both p<0.01).
Incubation of HIPF fibrotic isolates with the ANGII receptor
antagonist saralasin reduced both TGF-β1
mRNA and active protein, suggesting that the constitutive
expression of AGT drives the higher expression of TGF-β1
by the HIPF cells. Consistent with this premise, treatment
of either the primary NLFs or the WI38 cell line with 10-7M
ANGII increased both TGF-β1
mRNA and soluble active TGF-β1
protein. Moreover, induction of the myofibroblast transition
in the IMR90 cell line with 2ng/ml TGF-β1
increased steady state AGT mRNA levels by realtime PCR (8-fold,
p<0.01) and induced expression of an AGT promoter-luciferase
reporter construct by over 10-fold (p<0.001). Antisense
oligonucleotides against TGF-β1
mRNA or TGF-β
neutralizing antibodies, when applied to the fibrotic HIPF
cells in serum-free medium, significantly reduced AGT expression.
In lung sections from IPF patient biopsies, immunoreactive
AGT/ANGI proteins were detected in myofibroblasts, epithelial
cells and presumptive alveolar macrophages. Together, these
data support the existence of an angiotensin/TGF-β1
“autocrine loop” in human lung myofibroblasts
and also suggest ANG peptide expression by epithelia and macrophages
in the IPF lung. These findings may explain the ability of
ACE inhibitors and ANG receptor antagonists to block experimental
lung fibrosis in animals, and support the need for evaluation
of these agents for potential treatment of human IPF. This
manuscript discusses the data described above and their implications
regarding IPF pathogenesis.
[Back to top]
Attenuation of Bleomycin-Induced Pulmonary Fibrosis
by Intratracheal Administration of Antisense Oligonucleotides
Against Angiotensinogen mRNA
X. Li, J. Zhuang, H. Rayford, H. Zhang, R. Shu and B.D.
Uhal
Apoptosis of alveolar epithelial cells (AECs) is believed
to be critical for the development of bleomycin (BLEO)-induced
pulmonary fibrosis. Previous studies showed that apoptosis
of alveolar epithelial cells in response to BLEO could be
abrogated by antisense oligonucleotides against angiotensinogen
(AGT) mRNA and requires angiotensin II (ANG II) synthesis
de novo [17]. In this study we hypothesized that
blockade of local pulmonary ANG II synthesis by intratracheal
(I.T.) administration of antisense oligonucleotides against
AGT mRNA might attenuate BLEO-induced apoptosis of AECs and
prevent pulmonary fibrosis. In a BLEO-induced rat model of
lung fibrosis, endogenous lung AGT was upregulated in
vivo as early as 3 hours after BLEO instillation, as
detected by RT-PCR, in situ hybridization and immunohistochemistry.
AGT mRNA and angiotensin peptides were localized in type II
alveolar epithelial cells and also colocalized with alpha-smooth
muscle actin (α-SMA),
a marker of myofibroblasts. Tagged antisense administered
I.T. was specifically accumulated by the lung relative to
liver and kidney, and localized primarily in the epithelium
of air-ways and cells within alveolar walls. The intratracheal
AGT antisense reduced BLEO–induced pulmonary fibrosis
measured by lung hydroxyproline assay, decreased lung AGT
and active caspase-3 proteins, and reduced the number of apoptotic
epithelial cells but had no effect on the serum ANG II concentration.
These data are consistent with the hypothesis that lung-derived
AGT and local pulmonary ANG II are required for BLEO-induced
pulmonary fibrosis, and suggest the possibility of antisense-based
manipulation of the local angiotensin system as a potential
treatment of fibrotic lung diseases.
[Back to top]
The Neurobiological Bases for the Pharmacotherapy of Nicotine
Addiction
V. Di Matteo, M. Pierucci, G. Di Giovanni, A. Benigno
and E. Esposito
Nicotine, the major psychoactive agent present in tobacco,
acts as a potent addictive drug both in humans and laboratory
animals, whose locomotor activity is also stimulated. A large
body of evidence indicates that the locomotor activation and
the reinforcing effects of nicotine may be related to its
stimulatory effects on the mesolimbic dopaminergic function.
Thus, it is now well established that nicotine can increase
in vivo DA outflow in the nucleus accumbens and the
corpus striatum. The stimulatory effect of nicotine on DA
release most probably results from its ability to excite the
neuronal firing rate and to increase the bursting activity
of DA neurons in the substantia nigra pars compacta (SNc)
and the ventral tegmental area (VTA), and from its stimulatory
action on DA terminals in the corpus striatum and the nucleus
accumbens. The neurochemical data are consistent with neuroanatomical
findings showing the presence of nicotinic acetylcholine receptors
(nAChRs) in the SNc, the VTA, and in projection areas of the
central dopaminergic system such as the corpus striatum and
the nucleus accumbens. Several lines of evidence indicate
that the reinforcing properties of drugs of abuse, including
nicotine, can be affected by a number of transmitter systems
which may act by modulating central dopaminergic function.
In this paper, the neurobiological mechanisms underlying nicotine
addiction will be reviewed, and the possible strategies for
new pharmacological treatments of nicotine dependence will
be examined.
[Back to top]
The Protease of Human T-Cell Leukemia Virus Type-1
is a Potential Therapeutic Target
J. Tözsér and I.T. Weber
Human T-cell leukemia virus type-1 (HTLV-1) is associated
with a number of human diseases. Although the mechanism by
which the virus causes diseases is still not known, studies
indicate that viral replication is critical for the development
of HTLV-1 associated myelopathy, and initial studies suggested
that blocking replication with reverse transcriptase inhibitors
had a therapeutic effect. Therefore, based on the success
of HIV-1 protease inhibitors, the HTLV-1 protease is also
a potential target for chemotherapy. Furthermore, mutated
residues in HIV-1 protease that confer drug resistance are
frequently seen in equivalent positions of other retroviral
proteases, like HTLV-1 protease. Therefore, comparison of
HTLV-1 and HIV-1 proteases is expected to aid the rational
design of broad spectrum inhibitors effective against various
retroviral proteases, including the mutant HIV-1 enzymes appearing
in drug resistance.
This review describes the characteristics of HTLV-1 protease,
makes comparison with HIV-1 protease, and discusses the status
of inhibitor development for the HTLV-1 protease.
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