Current Drug Targets - Cardiovascular & Haematological Disorders, Volume 5, Number 4, 2005
Contents
Endothelial Progenitor Cells
as Potential Drug Targets Pp.277-286
T. Thum and J.
Bauersachs
Endothelin Receptor Antagonists:
Another Potential Alternative for Cardiovascular Diseases Pp.287-301
Rita C. A.
Tostes and Marcelo N. Muscara
Monocyte Cyclooxygenase-2
Activity: A New Therapeutic Target for Atherosclerosis? Pp.303-311
J.A. Paramo, J.A. Rodriguez, O. Beloqui and J. Orbe
Drug Eluting Stents in
Interventional Cardiology – Current Evidence and Emerging Uses Pp.313-321
N. Swanson and A.H. Gershlick
The Na+/H+
Exchanger: A Target for Cardiac Therapeutic Intervention Pp.323-335
M. Karmazyn, M. Sawyer and L. Fliegel
Reviewing the Cardiovascular
Complications of HIV Infection After the Introduction of Highly Active
Antiretroviral Therapy Pp.337-343
G. Barbaro
Imaging of Visceral Adipose
Tissue: An Emerging Diagnostic Tool and Therapeutic Target Pp.345-353
G. Iacobellis
Abstracts
[Back to top] Endothelial Progenitor Cells as Potential Drug Targets
T. Thum and J.
Bauersachs
Endothelial progenitor cells (EPC) are bone marrow derived cells with
the potential to differentiate into mature functional endothelial cells. First
clinical trials have been performed investigating the effects of EPC
transplantation into cardiac ischemic areas after myocardial infarction, in
patients with peripheral atherovascular disease or on endothelialisation of
artificial heart valves. Next to EPC transplantation, the pharmacological
mobilisation and functional modification of EPC may also play a major role in
future therapies. Studies have raised the concern that patients with coronary
heart disease or severe heart failure may suffer from decreased amounts and
impaired function of peripheral circulating EPC. Drug induced mobilization of
EPC and normalization of EPC function may therefore improve prognosis of certain
cardiovascular diseases. The underlying molecular events of a disturbed
mobilisation, differentiation, homing and/or function of EPC are not well
understood. In the present review we will highlight the current knowledge of
the role of EPC dysfunction in various cardiovascular diseases and focus on
potential causally related molecular mechanisms, which might be novel drug
targets.
[Back to top] Endothelin Receptor Antagonists:
Another Potential Alternative for Cardiovascular Diseases
Rita C. A.
Tostes and Marcelo N. Muscara
Endothelin-1 (ET-1), the predominant isoform of the endothelin peptide
family, has potent vasoconstrictor, mitogenic, pro-inflammatory and antinatriuretic
properties which have been implicated in the pathophysiology of a number of
cardiovascular diseases. ET-1 effects are mediated through activation of the
G-protein-coupled ETA and ETB receptors, which are found in a variety of cells
including endothelial, vascular smooth muscle and mesangial cells.
Overexpression of ET-1 has been consistently described in salt-sensitive models
of hypertension and in models of renal failure, and has been associated with
disease progression. The development of a range of peptidic and nonpeptidic
ET-1 receptor antagonists represents an exciting breakthrough in cardiovascular
therapeutics. Endothelin antagonists improve endothelium-dependent relaxation
and ameliorate vascular and cardiac hypertrophy as well as glomerulosclerosis;
interestingly, these beneficial effects seem to occur independently of their
capacity to lower blood pressure. The comparison between selective ETA and
combined ETA/ETB antagonists in experimental models of cardiovascular diseases
reveals no differences in terms of their effects on blood pressure, LV
hemodynamics or remodeling. In the case of salt-sensitive hypertension, ETA
receptor blockade leads to the prevention of vascular hypertrophy and renal
function improvement, being likely that these effects are also mediated by ETB
receptors based on the fact that the concomitant blockade of ETB receptors
prevents the beneficial effects of ETA antagonists. As a whole, the available
data indicate that the use of ET-1 receptor antagonists might be of therapeutic
interest to prevent hypertension induced end-organ damage; however, the
comparative efficacy of selective ETA vs. dual ETA/ETB blockade to prevent
target organ injuries in humans still remains to be investigated.
[Back to top] Monocyte Cyclooxygenase-2
Activity: A New Therapeutic Target for Atherosclerosis?
J.A. Paramo,
J.A. Rodriguez, O. Beloqui and J. Orbe
It is now widely accepted that atherosclerosis is a complex chronic inflammatory
disorder of the arterial tree associated with several risk factors. From the
initial phases of leukocyte recruitment to eventual rupture of vulnerable
atherosclerotic plaques, a low-grade inflammation, also termed
microinflammation, appears to play a key pathogenetic role. Experimental and
clinical evidence suggests that cyclooxygenase-2 (COX-2), an enzyme which
catalyzes the generation of prostaglandins from arachidonic acid, also
contributes to lesion formation. COX-2 has been detected in macrophages, smooth
muscle cells and endothelial cells in human atherosclerotic lesions. Several
studies have also reported the presence of COX-2 in the shoulder region of
atherosclerotic plaques, mainly colocalizing with macrophages and MMPs, enzymes
that are involved in the destabilization of atherosclerotic plaques, leading to
rupture and atherothrombotic syndromes (i.e. acute myocardial infarction).
We have recently assessed monocyte COX-2 activity and the production of
PGE2 in a population of apparently healthy subjects free from
clinically overt atherosclerosis. We found an association between increased PGE2
and increasing number of cardiovascular risk factors and carotid intima-media
thickness, a noninvasive surrogate marker of atherosclerosis, independently of
traditional and non traditional cardiovascular risk factors. Our findings
support the notion that the COX-2/PGE2 axis may have a role in
atherosclerosis, and this might be an attractive therapeutic target.
COX-2 inhibitors, collectively called coxibs (celecoxib, rofecoxib,
valdecoxib, lumiracoxib, etc), held a promise of improved treatment of
arthritis without the gastrointestinal side effects associated with aspirin and
other nonsteroidal anti-inflammatory drugs. However, clinical studies raise
several clinically relevant questions as to their beneficial role in
atherosclerosis prevention, because of increased thrombogenicity and
cardiovascular risk. Only well designed large scale clinical trials can provide
the answer as to the net effect of selective COX-2 inhibition on cardiovascular
events before this new class of anti-inflammatory drugs can be incorporated
into the armamentarium of atherosclerosis.
[Back to top] Drug Eluting Stents in
Interventional Cardiology – Current Evidence and Emerging Uses
N. Swanson and
A.H. Gershlick
Intervention in coronary artery disease is an area of cardiology where
novel drugs, in the form of drug-eluting stents (DES), are being used
increasingly commonly. DES are used across the whole range of coronary
intervention, from stable angina patients with single or multivessel disease,
acute coronary syndromes and acute myocardial infarction (i.e. primary
angioplasty). Most recently, they are being tested in a particularly
challenging subset of patients, those experiencing symptoms due to restenosis
within a previously stented area of vessel (in-stent restenosis, ISR).
This article summarises the rationale for the use of DES, across all
these areas, focussing specifically on the emerging results of trials and
registries examining the effectiveness of DES in acute myocardial infarction
(AMI) and ISR.
Drug-eluting stents represent a significant shift in the use of
locally-delivered drugs in interventional cardiology. On the basis of encouraging
trial data, including in the specific areas of in-stent restenosis and
myocardial infarction, their use is becoming extremely widespread in place of
bare-metal (drug-free) stents. This change is happening despite their high
costs, relatively short follow-up data and concerns of possible unwanted
effects, because of the weight of evidence that they are superior in preventing
restenosis in many patient groups. This reduction is highly significant in
angiographic terms and, to a lesser degree, in the prevention of clinically
important restenosis requiring revascularisation, but not clearly in terms of
overall mortality.
[Back to top] The Na+/H+
Exchanger: A Target for Cardiac Therapeutic Intervention
M. Karmazyn, M.
Sawyer and L. Fliegel
The Na+/H+ exchanger (NHE) is a ubiquitous
protein present in mammalian cells. In higher eukaryotes this integral membrane
protein removes one intracellular H+ for one extracellular Na+ protecting cells from intracellular acidification. NHE is of essential importance in the myocardium.
It prevents intracellular acidosis that inhibits contractility. NHE also plays a key role in damage to the
mammalian myocardium that occurs during ischemia and reperfusion and is involved in hypertrophy of the myocardium. NHE is
composed of a membrane bound domain of approximately 500 amino acids plus a
hydrophilic regulatory cytoplasmic domain of approximately 315 amino acids. The
NHE1 isoform is the only significant plasma membrane isoform present in the
myocardium. The activity of NHE1 is elevated in animal models of myocardial
infarcts and in left ventricular hypertrophy. During ischemia and reperfusion
of the myocardium, NHE activity catalyzes increased uptake of intracellular
sodium. This in turn is exchanged for extracellular calcium by the Na+/Ca2+
exchanger resulting in calcium overload and damage to the myocardium. Numerous
inhibitors of NHE have been developed to attempt to break this cycle of calcium
overload. In animal models excellent success has been obtained in this regard.
However in humans, clinical trials have resulted in only modest success and
recently, significant detrimental side effects were note of one NHE inhibitor.
The mechanisms by which these inhibitors affect NHE activity are presently
being investigated and regions of the protein important in NHE activity and
inhibitor efficacy are related but not identical. Future studies may develop
superior inhibitors that may circumvent recently reported side effects.
Recently, NHE inhibition has been shown to be remarkably effective in
preventing hypertrophy in some animal models. Whether this proves to be a
practical treatment for hypertrophy in humans has yet to be determined.
[Back to top] Reviewing the Cardiovascular
Complications of HIV Infection After the Introduction of Highly Active
Antiretroviral Therapy
G. Barbaro
Studies published before the introduction of highly active
antiretroviral therapy (HAART) have tracked the incidence and course of human
immunodeficiency virus (HIV) infection in relation to cardiac disease.The introduction
of HAART regimens, by preventing opportunistic infections and reducing the
incidence of myocarditis, has reduced the prevalence of HIV-associated
cardiomyopathy of about 30% and the prevalence of cardiac involvement of
AIDS-associated malignancies of about 50%. However, HAART regimens, especially
those including protease inhibitors have been shown to cause, in a high
proportion of HIV-infected patients, a metabolic syndrome
(lipodystrophy/lipoatrophy, dyslipidemia, type 2 diabetes mellitus, insulin
resistance) that may be associated with an increased risk of cardiovascular
disease (approximately 1.4 cardiac events per 1000 years of therapy according
to the Framingham score). A careful stratification of the cardiovascular risk
and cardiovascular monitoring of patients under HAART according to the most
recent clinical guidelines is needed.
[Back to top] Imaging of Visceral Adipose
Tissue: An Emerging Diagnostic Tool and Therapeutic Target
G. Iacobellis
Several lines of evidence support the contention that excess visceral
fat plays a significant role in the development of an unfavourable metabolic
and cardiovascular risk profile. Hence, estimation of visceral adipose tissue
(VAT), that is, the fat surrounding the internal organs, might be important for
cardiovascular risk stratification. Classically, anthropometric measures have
been employed to assess body fat distribution for risk assessment. But more
recently, imaging methods for visceral fat quantitation have become a focus of
attention particularly in a clinical research setting. Several imaging methods
have evolved for estimation of VAT mass. Among these, magnetic resonance
imaging (MRI) is fairly well established, but ultrasound and magnetic resonance
spectroscopy (MRS) are also emerging as useful methods for quantitation of VAT
and fat tissue content in vivo. Ultrasound is the most cost-effective
and a convenient imaging tool whereas MRS is still in its infancy but it is
highly promising because of its high sensitivity and specificity. There is a
compelling need to quantify VAT not only for diagnostic purposes, but also for
therapeutic interventions with weight reduction drugs or pharmaceuticals
targeted to with adipose tissue. For example, changes in regional fat
distribution can be used to estimate drugs effectiveness and their mechanism of
action. Therefore, in this review I shall present briefly latest and main
imaging techniques to detect the visceral adiposity, including the new
ultrasound measurements of different visceral adipose tissue compartments. Some
visceral adipose tissues which are not traditionally assessed, such as
intraperitoneal, mediastinal and the relatively small depots, such as
epicardial adipose tissue have also been recently studied and are now proposed
as new markers of visceral adiposity.