Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 26, 2007
Contents
The Search for Novel Anti-Thrombotic Drug Targets
Executive Editor: Dermot Cox
Editorial Pp. 2638-2639
Insights Into the Platelet Releasate Pp.
2640-2646
J.A. Coppinger and P.B. Maguire
[Abstract]
Recent Advances in the Characterisation of the Platelet
Membrane System by Proteomics Pp. 2647-2655
M. Foy and P.B. Maguire
[Abstract]
Growth Arrest Specific Gene (GAS) 6 Modulates Platelet
Thrombus Formation and Vascular Wall Homeostasis and Represents
an Attractive Drug Target Pp. 2656-2661
A.O. Maree, H. Jneid, I.F. Palacios, K. Rosenfield, C.A.
Macrae and D.J. Fitzgerald
[Abstract]
Finding Drug Targets Through Analysis of the Platelet
Transcriptome Pp. 2662-2667
J. McRedmond
[Abstract]
The Role of Hypoxia and Platelets in Air Travel-Related
Venous Thromboembolism Pp. 2668-2672
A. Bradford
[Abstract]
Collagen Receptors as Potential Targets for Novel
Anti-Platelet Agents Pp. 2673-2683
K.J. Clemetson and J.M. Clemetson
[Abstract]
Inhibition of Platelet Glycoprotein Ib and Its Antithrombotic
Potential Pp. 2684-2697
K. Vanhoorelbeke, H. Ulrichts, G. Van de Walle, A. Fontayne
and H. Deckmyn
[Abstract]
Pathogenesis and Treatment of Diabetic Complications,
Retinopathy, Nephropathy and Cardiomyopathy
Executive Editor: J.L. Wilkinson-Berka
Editorial Pp. 2698
Neuronal and Glial Cell Abnormality as Predictors
of Progression of Diabetic Retinopathy Pp. 2699-2712
E.L. Fletcher, J.A. Phipps, M.M. Ward, T. Puthussery and
J.L. Wilkinson-Berka
[Abstract]
The Podocyte: a Potential Therapeutic Target in Diabetic
Nephropathy Pp. 2713-2720
S.M. Marshall
[Abstract]
Angiotensin II and the Cardiac Complications of Diabetes
Mellitus Pp. 2721-2729
K.A. Connelly, A.J. Boyle and D.J. Kelly
[Abstract]
ACE2 and Diabetic Complications Pp. 2730-2735
R.G. Dean and L.M. Burrell
[Abstract]
PPARs and Diabetes-Associated Atherosclerosis
Pp. 2736-2741
A.C. Calkin, K.A. Jandeleit-Dahm, E. Sebokova, T.J. Allen,
J. Mizrahi, M.E. Cooper and C. Tikellis
[Abstract]
Abstracts
[Back to top]
Editorial: The Search for Novel Anti-Thrombotic
Drug Targets
Atherosclerosis is the leading cause of death in the Western
world and anti-thrombotic therapy plays a key role in the
management of this disease. However, despite the importance
of platelets in the disease process there has been little
progress in developing novel anti-thrombotic agents. Current
anti-thrombotic therapy revolves around aspirin, a drug that
has been around for thousands of years. More recently GPIIb/IIIa
antagonists were hailed as the future of anti-thrombotic therapy.
However, with the failure of the oral GPIIb/IIIa antagonists
[1] these drugs have been restricted to high-risk patients
under-going interventions [2]. Clopidogrel has proven to be
a significant breakthrough as it is orally active and is very
effective at inhibiting platelet aggregation [3].
So do we need another anti-platelet agent? There is convincing
evidence for aspirin resistance and this has been shown to
be associated with poor outcome in cardiovascular patients
[4]. The requirement for intravenous administration has restricted
the use of GPIIb/IIIa antagonists. Clopidogrel is the most
effective anti-platelet agent available today however, there
are problems associated with its use. Patients who have had
a stent implanted can develop in-stent thrombosis even when
on clopidogrel [5]. Since this can be fatal there is a definite
need for more effective anti-thrombotic agents.
There are three potential reasons for the failure of aspirin
and clopidogrel to prevent thrombosis. The first is due to
underdosing. The recommendations for the use of clopidogrel
have all moved towards increased loading dose and to extending
the treatment period [6]. A second potential problem is inherent
resistance to the effect of anti-platelet agents. There is
evidence that some people do not respond to aspirin and continue
to have normal platelet function despite aspirin therapy [7,
8]. A similar phenomenon appears to exist with clopidogrel
although not as well characterized. Some patients appear to
be resistant to both anti-platelet agents [9]. A third limitation
with aspirin and clopidogrel is their mechanism of action.
Aspirin acts to inhibit cyclooxygenase-mediated events while
clopidogrel inhibits ADP-mediated events. However, non-COX
and non-ADP-mediated events can occur as well. Thrombin will
activate platelets in a COX-independent manner and does not
require ADP for its action although secreted ADP may enhance
its actions. Thus, existing anti-platelet agents may be effective
in situations where there is collagen exposure but would be
ineffective if thrombin generation is occurring.
While there is a case to be made for the development of new
anti-platelet agents improved versions of aspirin or clopidogrel
are unlikely to be effective as they will still be limited
by their mechanism of action. Thus it is necessary to identify
novel drug targets. There are two approaches that can be used.
The first is to target proteins that are known to play a role
in thrombus formation. The second approach is to identify
novel proteins that may be involved. In this issue we look
at both approaches to developing new platelet drug targets.
One key receptor in platelet function is GPIb. It is well
known to mediate platelet adhesion to von Willebrand factor
under high shear. Since thrombosis in the coronary vessels
usually occurs in a high shear environment the GPIb-vWf interaction
is an ideal target. It also promises to be free of the major
adverse effect of other anti-thrombotics as it should not
prolong bleeding as this usually occurs in a low shear environment.
Many companies have tried to develop inhibitors of this interaction
with little success. Hans Deckmyn’s group in Leuven,
Belgium has many years of experience working with GPIb. Karen
Vanhoorelbeke from this group writes about the progress in
developing inhibitors of GPIb. In most cases these are antibodies
or proteins which will restrict them to acute use. However,
this is not necessarily a problem since these agents will
only inhibit the initial step of platelet adhesion and will
have no effect on thrombus growth. Thus they are likely to
be most effective when given early such as prior to angioplasty.
Another promising target is the collagen receptors. The interaction
between platelets and collagen is central to thrombus formation
and thus is an ideal drug target. However, there are two different
collagen receptors and we are only beginning to understand
the interplay between the two and their role in thrombosis.
The review by Ken and Jeannine Clemetson from University of
Berne, Switzerland provides a good insight into the collagen
receptors and their potential as drug targets.
Gas6 is a ligand for tyrosine kinase receptors and is an attractive
drug target. As well as playing a key role in atherosclerosis
it is also important in thrombosis. Drugs that inhibit the
interaction of Gas6 with its receptors have the potential
of both reducing atherosclerosis and thrombus formation simultaneously.
Andrew Maree of Massachusetts General Hospital, Boston, USA
reviews the role of Gas6 in thrombosis and suggests that its
role in both atherosclerosis and thrombosis my make it an
ideal drug target.
To develop novel drug targets it is necessary to know what
proteins are present in platelets. James McRedmond from University
College Dublin, Ireland reviews the use of genomics to identify
all of the transcripts present in platelets. This enables
us to compare the proteins present in platelets with those
of other cells and even to identify platelet-specific proteins.
However, there are problems associated with this approach
as only those proteins with stable mRNA will be detected,
thus many proteins may be missed.
As an alternative to transcriptomics a proteomics approach
can be used to identify the proteins expressed in a platelet.
While whole cell proteomics can provide a detailed list of
available proteins it can often miss less abundant proteins.
One approach described by Martina Foy and Patricia Maguire
from Conway Institute, University College Dublin Ireland is
to apply the proteomics approach to specific cellular compartments.
They focused on platelet lipid rafts which have been shown
to be essential in the signaling process. This approach is
more likely to identify essential proteins involved in the
activation process and has identified novel signaling proteins
not known previously to be in lipid rafts of any cell.
Thrombus formation is not the only function of platelets.
They secrete a large number of biologically active substances
such as ADP and serotonin many of which are well known. However
Judith Coppinger from Scripps, California and Patricia Maguire
from Conway Institute, UCD, Ireland used a proteomics approach
to characterize the platelet relesate. In fact over 300 proteins
have been shown to be secreted by platelets in response to
activation many of these are prothrombotic or pro-inflammatory.
In this issue we also have a new section on platelets in disease
that aims to show the importance of platelets in many disease
processes. Deep-vein thrombosis during long-haul flights has
been the subject of extensive media coverage recently and
has serious implications for the airline industry. In this
issue Aidan Bradford from The Royal College of Surgeons in
Ireland looks at the potential role of platelets in DVT and
the role hypoxia may play in this.
References
[1] Cox D. Oral GPIIb/IIIa antagonists: what went wrong? Curr
Pharm Des 2004; 10: 1587-96.
[2] Curtin R. Intravenous glycoprotein IIb/IIIa antagonists:
their benefits, problems and future developments. Curr Pharm
Des 2004; 10: 1577-85.
[3] Curtin R, Cox D, Fitzgerald D. Clopidogrel and Ticlopidine
In Platelets, A. D. Michelson, ed.; Academic Press, 2002,
pp. 787-801.
[4] Hankey GJ, Eikelboom JW. Aspirin resistance. The Lancet
2006; 367: 606-617.
[5] Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM,
Stankovic G, et al. Incidence, predictors, and outcome of
thrombosis after successful implantation of drug-eluting stents.
J Am Med Assoc 2005; 293: 2126-30.
[6] Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G,
Gorchakova O, Schomig A. Loading with 600 mg clopidogrel in
patients with coronary artery disease with and without chronic
clopidogrel therapy. Circulation 2004; 110: 1916-9.
[7] Maree AO, Curtin RJ, Chubb A, Dolan C, Cox D, O'Brien
J, et al. Cyclooxygenase-1 haplotype modulates platelet response
to aspirin. J Thrombosis Haemostasis 2005; 3: 2340-2345.
[8] Maree AO, Curtin RJ, Dooley M, Conroy RM, Crean P, Cox
D, et al. Platelet response to low-dose enteric-coated aspirin
in patients with stable cardiovascular disease. J Am Coll
Cardiol 2005; 46: 1258-63.
[9] Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J,
DeLao T, et al. Aspirin and clopidogrel drug response in patients
undergoing percutaneous coronary intervention: the role of
dual drug resistance. J Am Coll Cardiol 2006; 47: 27-33.
Dermot Cox
Molecular and Cellular Therapeutics
Royal College of Surgeons in Ireland
Dublin
Ireland
[Back to top]
Insights Into the Platelet Releasate
J.A. Coppinger and P.B. Maguire
The platelet releasate comprises of a multitude of inflammatory
and vasoactive substances, which can attract atherogenic leukocytes
from the circulation, activate endothelial cells and stimulate
vessel growth and repair by triggering vascular cell proliferation,
migration, and inflammation. Thus, platelets are believed
central in the development and progression of atherosclerotic
lesions and recent progress in uncovering more than 300 proteins
in the thrombin-activated platelet releasate may advance our
ability to understand the events involved and responses triggered
in the progression of atherosclerosis. Furthermore, neutralisation
of these platelet-derived pro-inflammatory factors may become
an interesting means for therapeutic or preventative intervention
in atherosclerosis.
[Back to top]
Recent Advances in the Characterisation of the Platelet
Membrane System by Proteomics
M. Foy and P.B. Maguire
Platelets are the principle effectors of cellular haemostasis
and key mediators in the pathogenesis of thrombosis. A variety
of membrane receptors determine platelet reactivity with numerous
agonists and adhesive proteins, and therefore represent key
targets for the development of antiplatelet drug therapy.
Here, we summarise recent advances in the analysis of the
complex platelet membrane system achieved through the integration
of platelet biology and proteomics.
[Back to top]
Growth Arrest Specific Gene (GAS) 6 Modulates Platelet
Thrombus Formation and Vascular Wall Homeostasis and Represents
an Attractive Drug Target
A.O. Maree, H. Jneid, I.F. Palacios, K. Rosenfield, C.A.
Macrae and D.J. Fitzgerald
GAS6, the product of growth arrest specific (GAS) gene 6 is
a ligand for the tyrosine protein kinase receptors Axl, Tyro3
and Mer whose signaling has been implicated in cell growth,
survival, adhesion and migration. Although a secreted human
vitamin K-dependent protein with close structural similarity
with protein S, GAS6 does not exhibit anticoagulant properties
but rather may be an important regulator of vascular homeostasis
and platelet signaling.
GAS6 signals via its receptor tyrosine kinases and
appears to modulate platelet outside-in signaling via
GP αIIbβIII,
playing a key role in the perpetuation of platelet aggregates
and clot retraction. GAS6 is also implicated in foam cell
formation and neointimal proliferation in response to vascular
injury. Thus GAS6 acts at key points in the pathophysiology
of atherosclerosis and thrombosis; two processes implicated
in most acute cardiovascular pathology. Inhibition of GAS6
or its receptors may provide antithrombotic activity in the
absence of increased bleeding and thus presents an attractive
drug target.
GAS6 signaling may be modulated through direct antibody inhibition,
blockade of its receptors or GAS6 trapping. However, ubiquitous
expression of GAS6 and its receptors and the diverse biological
effects of the pathway may make selective drug targeting difficult.
[Back to top]
Finding Drug Targets Through Analysis of the Platelet
Transcriptome
J. McRedmond
Recent studies of the platelet transcriptome have shown it
to be complex and readily analysed by modern techniques. Among
the thousands of distinct transcripts are many not previously
described in platelets. Differences in message abundance between
groups are apparent, and these are reflected at the protein
level. Platelets are enriched in messages for receptors, signal
transduction proteins and cytokines. Categories of potential
drug targets include novel receptors mediating platelet activation
and proteins involved in signal transduction. In addition,
proteins released or secreted by activated platelets, or specifically
translated from mRNA following platelet activation represent
a new category of potential drug target for the treatment
and prevention of thrombosis and atherogenesis. Transcriptional
studies provides a means for the identification and characterisation
of novel platelet drug targets in all these categories.
[Back to top]
The Role of Hypoxia and Platelets in Air Travel-Related
Venous Thromboembolism
A. Bradford
Although somewhat controversial, there is good evidence that
long-distance travel in general is a risk factor for venous
thromboembolism, even in the absence of other risk factors.
This is probably due to effects consequent to prolonged sitting
but air travel in particular may be associated with risk factors
other than this. One likely factor is hypoxia caused by the
low ambient pressure of aircraft cabins. There is an association
between venous thromboembolism and the hypoxia of altitude,
chronic respiratory disease, neonatal hypoxia, sleep apnoea
and experimentally-induced hypoxia. Platelet number and/or
function are altered in all of these circumstances. Platelet
aggregation is pivotal to venous thromboembolism and hypoxia
alters platelet number and function. The early-onset thrombocytosis
caused by hypoxia may be due to increased release of platelets
from megakaryocytes and the late-onset thrombocytopaenia may
be due to decreased platelet production and/or stem cell competition
between erythrocytes and megakaryocytes. Hypoxia-induced platelet
activation and aggregation may be due to increased circulating
catecholamine levels but it is not known whether hypoxia can
affect platelets directly. There is a need for further studies
on the possible involvement of hypoxia-induced changes in
platelet number and function in air travel-related venous
thromboembolism.
[Back to top]
Collagen Receptors as Potential Targets for Novel
Anti-Platelet Agents
K.J. Clemetson and J.M. Clemetson
Platelets have important roles in atherosclerosis and thrombosis
and their inhibition reduces the risk of these disorders.
There is still a need for platelet inhibitors affecting pathways
that reduce thrombosis and atherosclerosis while leaving normal
hemostasis relatively unaffected, thus reducing possible bleeding
complications. Although combinations show progress in achieving
these goals none of the present inhibitors completely fulfill
these requirements. Collagen receptors offer attractive possibilities
as alternative targets at early stages in platelet activation.
Three major collagen receptors are assessed in this review;
the α2β1
integrin, responsible primarily for platelet adhesion to collagen;
GPVI, the major signaling receptor for collagen; and GPIb-V-IX,
which is indirectly a collagen receptor via von Willebrand
factor. Several thrombosis models and experimental approaches
suggest that all three are interesting targets and merit further
investigation.
[Back to top]
Inhibition of Platelet Glycoprotein Ib and Its Antithrombotic
Potential
K. Vanhoorelbeke, H. Ulrichts, G. Van de Walle, A. Fontayne
and H. Deckmyn
The platelet receptor glycoprotein (GP)Ib-IX-V complex plays
a dominant role in the first steps of platelet adhesion and
arterial thrombus formation. Through its interaction with
the multimeric plasma protein von Willebrand factor (VWF),
which is bound to the damaged subendothelial structures, GPIb-IX-V
tethers the platelets from the flowing blood thereby slowing
them down. This step is a prerequisite for the collagen receptors
to participate in firm adhesion resulting in the formation
of a first platelet layer which is the basis for further thrombus
formation. Recently, other ligands for GPIb-IX-V besides the
extensively studied VWF have been identified, such as : α-thrombin,
coagulation factor XII (FXII), high molecular weight kininogen
(HMWK), factor XI (FXI), integrin Mac-1 and P-selectin. In
this review, the interaction of GPIb-IX-V with its different
ligands is described and the anticipated or demonstrated in
vivo effects are discussed.
[Back to top]
Editorial: Pathogenesis and Treatment of Diabetic
Complications, Retinopathy, Nephropathy and Cardiomyopathy
This issue of Current Pharmaceutical Design, for which I have
the great pleasure to be Executive Guest Editor, addresses
topical issues relating to the pathogenesis and treatment
of diabetic complications, retinopathy, nephropathy and cardiomyopathy.
Fletcher et al. [1] describes neuronal and glial
cell dysfunction in diabetic retinopathy, and how these changes
relate to vascular compromise.
Marshall [2] discusses the importance of the podocyte in the
development of diabetic nephropathy, and how a variety of
factors including metabolic and hemodynamic abnormalities
affect podocyte integrity.
Connelly et al. [3] examines the prevalence of coronary
artery disease and cardiac failure in the diabetic population,
and how factors such as angiotensin II are crucial for the
development of diabetic cardiac disease.
Dean and Burrell [4] examines the role of the recently identified
enzyme, ACE2, in microvascular and macrovascular disease in
diabetes, and how compounds that target ACE2 may potentially
be of clinical value for the treatment of diabetic complications.
Calkin et al. [5] reviews evidence that PPARα
agonists have potential benefits for the treatment of diabetes-associated
atherosclerosis.
Given the excellence of the reviews in this issue, I hope
the readers of Current Pharmaceutical Design will find this
issue informative with regard to updating their knowledge
about the variety of factors implicated in the development
and progression of diabetic complications. The reviews identify
the potential for the development of new and improved treatment
strategies for the better management of diabetic micro- and
macro-vascular disease.
References
[1] Fletcher EL, Phipps JA, Ward MM, Puthussery T, Wilkinson-Berka
JL. Neuronal and Glial Cell Abnormality as Predictors of Progression
of Diabetic Retinopathy. Curr Pharm Des 2007; 13(26): 2699-2712.
[2] Marshall SM. The Podocyte: a Potential Therapeutic Target
in Diabetic Nephropathy. Curr Pharm Des 2007; 13(26): 2713-2720.
[3] Connelly KA, Boyle AJ, Kelly DJ. Angiotensin II and the
Cardiac Complications of Diabetes Mellitus. Curr Pharm Des
2007; 13(26): 2721-2729.
[4] Dean RG, Burrell LM. ACE2 and Diabetic Complications.
Curr Pharm Des 2007; 13(26): 2730-2735.
[5] Calkin AC, Jandeleit-Dahm KA, Sebekova E, Allen TJ, Mizrahi
J, Cooper ME, Tikellis C. PPARs and Diabetes-Associated Atherosclerosis.
Curr Pharm Des 2007; 13(26): 2736-2741.
Jennifer L. Wilkinson-Berka
Department of Immunology
Monash University
Commercial Rd, Prahran,
Victoria 3004, Australia
[Back to top]
Neuronal and Glial Cell Abnormality as Predictors
of Progression of Diabetic Retinopathy
E.L. Fletcher, J.A. Phipps, M.M. Ward, T. Puthussery and
J.L. Wilkinson-Berka
Diabetes is known to cause significant alterations in the
retinal vasculature. Indeed, diabetic retinopathy is the leading
cause of blindness in those of working age. Considerable evidence
is emerging that indicates that retinal neurons are also altered
during diabetes. Moreover, many types of neuronal deficits
have been observed in animal models and patients prior to
the onset of vascular compromise. Such clinical tools as the
flash ERG, multifocal ERG, colour vision, contrast sensitivity
and short-wavelength automated perimetry, all provide novel
means whereby neuronal dysfunction can be detected at early
stages of diabetes. The underlying mechanisms that lead to
neuronal deficits are likely to be broad. Retinal glial cells
play an essential role in maintaining the normal function
of the retina. There is accumulating evidence that Müller
cells are abnormal during diabetes. They are known to become
gliotic, display altered potassium si-phoning, glutamate and
GABA uptake and are also known to express several modulators
of angiogenesis. This review will examine the evidence that
neurons and glia are altered during diabetes and the relationship
these changes have with vascular compromise.
[Back to top]
The Podocyte: a Potential Therapeutic Target in Diabetic
Nephropathy
S.M. Marshall
Over the last five years, much work has underlined the important
role of the podocyte in the development of diabetic nephropathy.
The metabolic and haemodynamic abnormalities of the diabetic
milieu act in concert, perhaps via the common effector
path of oxidative stress and development of reactive oxygen
species, to promote podocyte damage. There is loss of nephrin
from the slit diaphragm, increased synthesis of some of the
components of the glomerular basement membrane, activation
of pro-apoptotic and hypertrophic pathways, loss of the α3β1integrin
and increased secretion of VEGF. These changes interact to
lead to increased permeability, accumulation of abnormal extracellular
matrix, apoptosis, foot process detachment and podocyte loss.
The foot processes of the remaining podocytes hypertrophy
and widen, with reduced filtration slit width. The end result
is increasing proteinuria, basement membrane thickening and
accumulation of mesangial matrix and declining renal function.
Some currently used therapies, such as tight glucose control
and inhibition of the renin angiotensin system, ameliorate
these changes and prevent podocyte loss. Statins may also
have a specific podocyte protective role. Other potential
therapies include inhibitors of glycation, antioxidants, and
inhibitors of growth factor and signalling pathways.
[Back to top]
Angiotensin II and the Cardiac Complications of Diabetes
Mellitus
K.A. Connelly, A.J. Boyle and D.J. Kelly
The prevalence of diabetes has reached epidemic proportions
in the developed world and is expect to increase to 5.4% by
2025. This has resulted in an unprecedented number of patients
experiencing the macro- and micro-vascular complications of
diabetes, such as renal, retinal, neurological and cardiac
dysfunction. Premature coronary artery disease and cardiac
failure are vastly over-represented in the diabetic population,
with significant morbidity and mortality. In fact, the rate
of cardiac events in patients with diabetes is equivalent
to non-diabetic patients with a previous myocardial infarction.
Epidemiological evidence, combined with the results of large
scale trials blocking the renin-angiotensin system (RAS) have
provided data to support the hypothesis that angiotensin II
and its interaction with the metabolic changes associated
with diabetes mellitus is responsible for the pathogenesis
of many of these complications. This review focuses on the
role of the RAS and the development of diabetic cardiac disease.
[Back to top]
ACE2 and Diabetic Complications
R.G. Dean and L.M. Burrell
Angiotensin converting enzyme (ACE) is a key enzyme in the
renin angiotensin system (RAS) and converts angiotensin (Ang)
I to the vasoconstrictor Ang II, which is thought to be responsible
for most of the physiological and pathophysiological effects
of the RAS. This classical view of the RAS was challenged
with the discovery of the enzyme, ACE2 which both degrades
Ang II and leads to formation of the vasodilatory and anti-proliferative
peptide, Ang 1-7. Activation of the RAS is a major contributor
to diabetic complications, and blockade of the vasoconstrictor
and hypertrophic actions of Ang II, slows but does not prevent
the progression of such complications. The identification
of ACE2 in the heart and kidney adds further complexity to
the RAS, provides the rationale to explore the role of this
enzyme in pathophysiological states, including the microvascular
and macrovascular complications of diabetes. It is believed
that ACE2 acts in a counter-regulatory manner to ACE to modulate
the balance between vasoconstrictors and vasodilators within
the heart and kidney, and may thus play a significant role
in the pathophysiology of cardiac and renal disease. Relatively
little is known about ACE2 in diabetes, and this review will
explore and discuss the data that is currently available.
The discovery of ACE2 presents a novel opportunity to develop
drugs that specifically influence ACE2 activity and/or expression,
and it is possible that such compounds may have considerable
clinical value in the prevention and treatment of the complications
of diabetes.
[Back to top]
PPARs and Diabetes-Associated Atherosclerosis
A.C. Calkin, K.A. Jandeleit-Dahm, E. Sebokova, T.J. Allen,
J. Mizrahi, M.E. Cooper and C. Tikellis
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent
transcription factors affecting the regulation of various
genes relevant to the pathogenesis of diabetic complications.
A number of drugs have been developed to act as agonists of
the three PPARs. To date, PPAR isoforms that have been identified
are the α,
β/δ,
and γ
isosforms. Fenofibrate and gemfibrozil are two drugs that
act as PPARα
agonists and are currently in use in the clinical setting.
Rosiglitazone is a PPARγ
agonist also in clinical use. These drugs have proved very
useful in regulation of either glucose or lipid metabolism
and consequently are used in patients with type 2 diabetes.
Here, we will review the anti-atherosclerotic potential of
PPAR agonists with particular emphasis on recent studies in
an animal model of diabetes-associated atherosclerosis, the
streptozotocin diabetic apolipoprotein E deficient mouse.
These studies have shown both PPARα
agonists, gemfibrozil and fenofibrate, confer anti-atherosclerotic
effects, partly independent of their metabolic effects. Similar
positive findings have also been detected in a dose-dependent
manner with the PPARγ
agonist, rosiglitazone. The potential clinical implications
of these findings are also discussed in view of the recently
reported results of the PROACTIVE and FIELD clinical trials
with the PPAR agonists rosiglitazone and fenofibrate respectively.
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