Cardiovascular
& Hematological Agents in Medicinal Chemistry
ISSN: 1871-5257
Cardiovascular & Hematological
Agents in Medicinal Chemistry
Volume 5, Number 4, October 2007
Contents
Inhibition of Renin-Angiotensin System and Advanced
Glycation End Products Formation: A Promising Therapeutic
Approach Targeting on Cardiovascular Diseases Pp.
249-264
A. Geronikaki, A. Gavalas, V. Dislian and G. Giannoglou
[Abstract]
The Role of Endothelial Progenitor Cells and Statins
in Endothelial Function: A Review Pp. 265-272
J.F. Gómez-Cerezo, B. Pagán-Muñoz,
M. López-Rodríguez, M. Estébanez-Muñoz,
and F.J. Barbado-Hernández
[Abstract]
Pharmacological Activity of Cardiovascular Agents
from Herbal Medicine Pp. 273-277
J.W. Ho and M. Jie
[Abstract]
Porphyrin-Photosensitized Processes: Their Applications
in the Prevention of Arterial Restenosis Pp. 278-288
M. Magaraggia, L. Marigo, A. Pagnan, G. Jori and A. Visonà
[Abstract]
Preclinical Testing of Drug-Induced Proarrhythmia:
Value of Transgenic Models Pp. 289-294
L. Fabritz, G. Breithardt and P. Kirchhof
[Abstract]
The Importance of Lost Minerals in Heart Failure
Pp. 295-299
K.P. Newman, M.T. Neal, M. Roberts, K.D. Goodwin, E.A.
Hatcher and S.K. Bhattacharya
[Abstract]
Targeting the Sarcolemmal Calcium Pump: A Potential
Novel Strategy for the Treatment of Cardiovascular Disease
Pp. 300-304
D. Oceandy, M.A. Mamas and L. Neyses
[Abstract]
von Willebrand Factor, von Willebrand Factor-Cleaving
Protease, and Shear Stress Pp. 305-310
P. Perutelli and A.C. Molinari
[Abstract]
Endocannabinoid Regulation of Matrix Metalloproteinases:
Implications in Ischemic Stroke Pp. 311-318
S. Mukhopadhyay and D.A. Tulis
[Abstract]
Developing Specific Therapeutic Strategies for Transfusion–Related
Acute Lung Injury. An Overview of Potentially Useful Animal
Models Pp. 319-326
A.P.J. Vlaar, M.M. Zweers, M.J. Schultz and N.P. Juffermans
[Abstract]
Abstracts
[Back to top]
Inhibition of Renin-Angiotensin System
and Advanced Glycation End Products Formation: A Promising
Therapeutic Approach Targeting on Cardiovascular Diseases
A. Geronikaki, A. Gavalas, V. Dislian and G. Giannoglou
Cardiovascular disease remains the leading cause of death
worldwide. The renin-angiotensin-aldosterone system (RAAS)
plays a key role in the regulation of blood pressure, through
the actions of angiotensin (Ang) II. Excessive RAAS activity
may lead to hypertension and associated target organ damage.
Indeed, RAAS blockade with angiotensin converting enzyme inhibitors
(ACEIs) and/or angiotensin receptor AT (1) blockers (ARBs)
has proved to be successful treatment for arterial hypertension,
heart failure and diabetes. Accumulating evidence suggests
that arterial stiffness is an important and independent predictor
of cardiovascular risk. More recently, a role for advanced
glycation end-products (AGEs) in the development of arterial
stiffening has been suggested. Advanced glycation end-products
form by a nonenzymatic reaction between reducing sugars and
biological proteins. Mechanisms underlying these alterations
include AGE cross-linking of collagen and AGE interactions
with circulating proteins and AGE receptors. New pharmacologic
agents that prevent AGE formation, break cross-links, or block
AGE receptors reduce vascular and myocardial stiffness, inhibit
atherosclerotic plaque formation, and improve endothelial
function. These agents promise to reduce the risk of isolated
systolic hypertension, diastolic dysfunction, diabetes and
thus, heart failure.
[Back to top]
The Role of Endothelial Progenitor Cells and Statins
in Endothelial Function: A Review
J.F. Gómez-Cerezo, B. Pagán-Muñoz,
M. López-Rodríguez, M. Estébanez-Muñoz,
and F.J. Barbado-Hernández
Endothelial dysfunction, a well recognized marker of cardiovascular
risk, is an early event in artheriosclerosis process. Diabetes
mellitus, hypertension and dyslipidemia, known risk factors
for coronary disease have been associated with endothelial
dysfunction, which improves after the control of these factors.
Statins have additional benefits on endothelial function not
related to decreasing cholesterol levels, known as pleiotropic
effects. Most recently it has been reported the effect of
statins promoting bone marrow-derived mononuclear cells. These
cells are positive for CD34 and KDR superficial markers of
endothelial cellular lineage, which is consistent with the
hypothesis that they constitute the endothelial progenitor
cells. Circulating endothelial progenitor cells are involved
in the repair process of the endothelium after endothelial-cell
injury in myocardial ischemia, angina and other stressful
situations. Recent studies have demon-strated an inverse relationship
between the EPC count in peripheral blood and risk of developing
a cardiovascular event. In addition, circulating EPC correlates
with the presence of endothelial dysfunction and could play
a role as a surrogate biologic marker in vascular function.
The effect of statins on endothelial progenitor cells might
contribute to improve en-dothelial function leading to a decrease
in vascular risk, independently of their impact on LDL cholesterol.
In this paper, we review the role of statins in EPC mobilization,
its effect in endothelial function restoration and the relevance
of this finding in cardiovascular risk. We also review future
therapeutic implications.
[Back to top]
Pharmacological Activity of Cardiovascular Agents
from Herbal Medicine
J.W. Ho and M. Jie
Some of the active phytochemicals in herbal medicine are finding
therapeutic use. For example, patients with heart disease
are reported to benefit from treatment with herbal medicine
with fewer side effects. Previous studies showed the inhibitory
effects of tetramethylpyrazine, an active component of medicinal
herb, on phosphodiesterase that is associated with heart disease
and the cardio-protective effects of other herbal medicine
that was used to protect ischemia-reperfusion injury of rat
hearts. Individual herbal medicines show antipyretic, analgesic
and anti-inflammatory and anti-cancer effects. In addition
to sharing many therapeutic activities, the active components
of herbal medicine are also used in nutrient supplement for
cardiovascular disease. Numerous in vitro studies
of herbal medicine on different cell lines and in vivo
study of herbal medicine have been reported. However,
the mechanism of actions remains unclear. The present review
aims to give an overview of the recent development of herbal
medicine in treatment of cardiovascular disease, and covers
the possible mechanism of action of some of active principles.
The study will provide insights into drug action and demonstrate
the therapeutic benefits of herbal medicine for the treatment
of cardiovascular disease.
[Back to top]
Porphyrin-Photosensitized Processes: Their Applications
in the Prevention of Arterial Restenosis
M. Magaraggia, L. Marigo, A. Pagnan, G. Jori and A. Visonà
Photodynamic therapy (PDT) is based on the use of a photozensitising
compound which is accumulated by rapidly proliferating cells.
Subsequent irradiation with light wavelengths specifically
absorbed by the photosensitiser promotes the generation of
reactive short-lived oxygen species which cause an irreversible
and selective damage. Endovascular interventions to correct
obstructive arterial disease have been developed worldwide
with excellent short term results. However, long term patency
is still limited by the onset of restenosis, due to subsequent
intimal hyperplasia (IH). IH is characterized by proliferation
and migration of smooth muscle cells (SMC) and extracellular
matrix production. Targeting of SMC by photozensitisers can
be efficiently achieved by taking advantage of the receptors
for low density lipoproteins (LDL) expressed by such cells.
Thus, preference is given to hydrophobic compounds which readily
partition in the lipid matrix of LDL. We developed a liposomal
formulation of a highly hydrophobic photozensitising agent,
Zn(II)-phthalocyanine (ZnPc). The liposome-delivered ZnPc
was readily taken up by cultured SMC cells and preferentially
localized in the Golgi apparatus. Red light irradiation of
incubated SMC induced cell death. Extension of these investigations
to an in vivo rabbit model showed that ZnPc mainly
accumulated in the media layer, where PDT induces the main
damage through cellular depletion due to apoptosis of SMC,
changes in the extracellular matrix with generation of a barrier
to cellular migration, and acceleration of re-endothelization.
Initial clinical applications showed that PDT safely and effectively
prevents restenosis after angioplasty up to a 6 month follow-up.
[Back to top]
Preclinical Testing of Drug-Induced Proarrhythmia:
Value of Transgenic Models
L. Fabritz, G. Breithardt and P. Kirchhof
Drug-induced proarrhythmia is a serious medical problem that
causes relevant morbidity and mortality. It is also a relevant
problem for the development of novel pharmacological compounds.
Therefore, there is a need for sensitive, specific and high-throughput
preclinical tests to detect a risk for drug-induced proarrhythmia
early in the development of new drugs. The review focuses
on the potential role of transgenic models with altered repolarisation
but without overt structural heart disease for drug-induced
proarrhythmia screening. Today, selected murine models with
alterations in K+, Na+
channels and ankyrin are available. In the future, transgenic
rabbit and Zebra fish models may also be used.
[Back to top]
The Importance of Lost Minerals in Heart Failure
K.P. Newman, M.T. Neal, M. Roberts, K.D. Goodwin, E.A.
Hatcher and S.K. Bhattacharya
The clinical syndrome congestive heart failure (CHF) has its
origins rooted in a salt-avid state mediated largely by effector
hormones of the renin-angiotensin-aldosterone system (RAAS).
In addition, a systemic illness accompanies chronic RAAS activation.
Its features include: the presence of oxidative stress in
diverse tissues coupled with a reduction in activity of endogenous
oxidoreductases, such as Cu/Zn-superoxide dismutase and Se-glutathione
peroxidase; a proin-flammatory phenotype with activated immune
cells and increased circulating levels of proinflammatory
cytokines; and a catabolic state with loss of soft tissues
and bone that eventuates in a wasting syndrome termed cardiac
cachexia. Pathogenic mechanisms and pathophysiologic expressions
of this illness are under active investigation.
In this context and less well appreciated is the importance
of a dyshomeostasis of various minerals, including Ca2+,
Mg2+, Zn, and Se, and their
impact on the systemic and progressive nature of CHF. A convergence
of multiple factors, some hormonal (e.g., aldosteronism, secondary
hyperparathyroidism, hypovitaminosis D), others pharmacologic
(e.g., loop diuretics, angiotensin-converting enzyme inhibitors),
predispose to the heightened excretion of these minerals in
urine and feces while parathyroid hormone promotes intracellular
Ca2+ overloading in diverse
tissues. The importance of these macro- and micronutrients
to the appearance of oxidative stress, compromised antioxidant
defenses, an immunostimulatory state and tissue wasting needs
to be critically addressed. So, too, must the potential for
nutriceuticals, complementary to today’s pharmaceuticals,
to assist in the overall management of CHF.
[Back to top]
Targeting the Sarcolemmal Calcium Pump: A Potential
Novel Strategy for the Treatment of Cardiovascular Disease
D. Oceandy, M.A. Mamas and L. Neyses
Intracellular calcium dynamics play a very important role
in mediating contraction and signalling in cardiomyocytes
and vascular smooth muscle cells. A number of calcium transporters
have been identified that orchestrate a complex process of
excitation-contraction coupling and molecular signalling.
Despite the variability of the calcium transporters expressed
in cardiomyocytes, most calcium channel blockers used therapeutically
target the L-type calcium channel and exhibit antihypertensive
and/or vasodilating activities. Recently, another calcium
pump which is located in the sarcolemma has been shown to
mediate cardiac contractility and vascular tone. Interestingly,
this sarcolemmal calcium pump (also known as Plasma Membrane
Calcium/calmodulin dependent ATPase or PMCA) exerts its function
not by altering global calcium concentration, but by mediating
signal transduction pathways. This review will discuss recent
advances that support the key roles of PMCA as signalling
molecule and the potential to target this calcium pump as
a novel approach for the treatment of cardiovascular disease.
[Back to top]
von Willebrand Factor, von Willebrand Factor-Cleaving
Protease, and Shear Stress
P. Perutelli and A.C. Molinari
von Willebrand factor (VWF) is a multimeric plasma glycoprotein
(GP) involved in platelet adhesion at the site of vascular
damage, which acts as a bridge between the injured subendothelium
and the platelet receptors. The multimeric structure of VWF
allows it to support multiple interactions with platelets
and endothelial components under high shear stress. Rapid
flow conditions induce a conformational transition of the
VWF molecule, thus allowing its functional bind-ing domains
to be exposed. A specific VWF-cleaving protease (ADAMTS-13)
physiologically down regulates the multimeric size of newly
released and circulating VWF in order to prevent unwanted
platelet thrombus formation. The occurrence of microvascular
platelet aggregation in thrombotic thrombocytopenic purpura,
which is caused by an ADAMTS-13 deficiency, well-demonstrates
the important role of the protease in regulating the adhesive
activity of VWF. Better knowledge of VWF function would contribute
to the development of novel anti-thrombotic strategies based
on the selective inhibition of the VWF interaction with platelet
receptors and endothelial components in areas of the circulation
characterised by elevated fluid dynamic forces.
[Back to top]
Endocannabinoid Regulation of Matrix Metalloproteinases:
Implications in Ischemic Stroke
S. Mukhopadhyay and D.A. Tulis
Stroke is a major cause of morbidity and mortality and follows
heart disease and cancer as the third leading cause of death
in Western societies [1]. Despite many advances in stroke
research and pharmacotherapy, clinical treatment of this debilitating
disorder is still inadequate. Recent findings from several
laboratories have identified the endocannabinoid signaling
pathway, comprised of the endocannabinoid agonist anandamide
and its pharmacological targets, CB1
and CB2 cannabinoid receptors
and associated anandamide receptors, as a physiological system
with capacity to mitigate cardiovascular and cerebrovascular
disorders through neuronal and endothelial actions. Variability
in experimental stroke models and modes of outcome evaluation,
however, have provoked controversy regarding the precise roles
of endocannabinoid signals in mediating neural and/or vascular
protection versus neurovascular damage. Clinical trials of
the CB1 antagonist rimonabant
demonstrate that modulation of endocannabinoid signaling during
metabolic regulation of vascular disorders can significantly
impact clinical outcomes, thus providing strong argument for
therapeutic utility of endocannabinoids and/or cannabinoid
receptors as targets for therapeutic intervention in cases
of stroke and associated vascular disorders. The purpose of
this review is to provide updated information from basic science
and clinical perspectives on endocannabinoid ligands and their
effects in the pathophysiologic genesis of stroke. Particular
emphasis will be placed on the endocannabinoids anandamide
and 2-arachidonylglycerol and CB1
receptor-mediated mechanisms in the neurovascular unit during
stroke pathogenesis. Deficiencies in our knowledge of endocannabinoids
in the etiology and pathogenesis of stroke, caveats and limitations
of existing studies, and future directions for investigation
will be addressed.
[Back to top]
Developing Specific Therapeutic Strategies for Transfusion–Related
Acute Lung Injury. An Overview of Potentially Useful Animal
Models
A.P.J. Vlaar, M.M. Zweers, M.J. Schultz and N.P. Juffermans
Transfusion–related (TR)- acute lung injury (ALI) is
the leading cause of transfusion–related morbidity and
mortality. The pathogenesis of TRALI is thought to be a “two
hit”–entity: the “first hit” is (any)
proinflammatory pulmonary condition (e.g., pneumonia, sepsis
or lung contusion) resulting in activation of lung endothelium
with sequestration of polymorphonuclear neutrophils –
the “second hit” is provided by transfusion of
a blood product. Either antibodies against neutrophils are
thought to be implicated in the activation of the sequestrated
neutrophils, or bioactive lipids (which accumulate during
storage of blood products) induce the “second hit”,
finally resulting in lung injury. Preventive measures do not
prevent all TRALI cases. Also, TRALI is most probably underdiagnosed.
In this review, we call for the development of therapeutic
approaches for this potentially life–threatening disease.
Several interventions which are beneficial in ALI and may
also be beneficial in TRALI are discussed. The application
of these interventions requires the development of clinically
relevant TRALI animal models. We discuss the present TRALI
animal models and their shortcomings and propose future animal
models, in which clinically relevant “first hits”
can be applied, thereby imitating the complex clinical situation.
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