|
Cardiovascular
& Hematological Disorders - Drug Targets
ISSN: 1871-529X
Current Drug Targets - Cardiovascular
& Hematological Disorders
Volume 8, Number 3, September 2008
Contents
Status of Cytokines in Ischemia Reperfusion Induced
Heart Injury Pp. 161-172
Ming Zhang and Li Chen
[Abstract]
Extra-Hematopoietic Effects of Erythropoietin
Pp. 173-178
Alain Cariou, Stéphanie André
and Yann-Erick Claessens
[Abstract]
Determinants of Perceived Severity of
Hypertension and Drug-Compliance in Hypertensive Patients
Pp. 179-184
Arie Dijkstra, Vanessa Okken, Menco Niemeijer
and Ton Cleophas
[Abstract]
Endothelial Progenitors in Vascular
Repair and Angiogenesis: How Many are Needed and What to do?
Pp. 185-193
Carla Real, Francisco Caiado and Sergio
Dias
[Abstract]
Soluble CD40L and its Role in Essential
Hypertension: Diagnostic and Therapeutic Implications
Pp. 194-202
Patrizia Ferroni and Fiorella Guadagni
[Abstract]
Lectin-Like Oxidized Low-Density Lipoprotein
Receptor-1 (LOX 1), a Relevant Target for Diabetic Vasculopathy?
Pp. 203-211
Geneviève Renie
[Abstract]
A More Accurate Approach to Molecular
Genetics Analysis in Vascular Disease Pp.
212-227
Jose Ignacio Lao Villadóniga
[Abstract]
Adipose Tissue: The Link Between Obesity
and Cardiovascular Disease Pp. 228-237
Vanessa DeClercq, Carla Taylor and
Peter Zahradka
[Abstract]
Abstracts
[Back to top]
Status of Cytokines in Ischemia Reperfusion Induced
Heart Injury
Ming Zhang and Li Chen
Extensive investigations have implicated cytokines
such as tumour necrosis factor (TNF)-α
and interleukin (IL) -1, and IL-6 as contributing to the pathology
of ischemia-reperfusion (I/R) injury, since an increase in
the production of those cytokines was clinically detected
after myocardial infarction and cardiopulmonary bypass surgery.
Current evidence indicates that these cytokines are autocrine
contributors to myocardial dysfunction and cardiomyocyte necrosis
in I/R injury, whereas, earlier evidence also suggest that
cytokines have controversial roles in cardiovascular pathophysiology.
Accordingly, it becomes vital to better define the mechanisms
of action of cytokines as important steps towards the development
of effective therapeutic strategies to combat their deleterious
effects in ischemia-induced myocardial injury. Since TNF-α,
TGF-β1,
IL-1, IL-6 and IL-8 have been frequently studied in cardiovascular
diseases, especially in I/R heart disease, the purpose of
this article is to review the cardiodepressant role of these
cytokines and their release in I/R injury.
[Back to top]
Extra-Hematopoietic Effects of Erythropoietin
Alain Cariou, Stéphanie André
and Yann-Erick Claessens
Erythropoietin (Epo) has a long-lasting history
as the hormon that allows production of red blood cells. It
is now well established that, besides erythropoiesis, Epo
has the ability to sustain proliferation of myeloid lineages.
More recently, extra-haematological roles have been described
for Epo. Its receptor, EpoR, has been detected at the membrane
of several neoplastic and normal cell types from the central
nervous system and other non haematological cell lines. Whereas
Epo-EpoR have been detected several years ago in some extra-haematological
normal lineages, their role has long been underestimated whereas
they may be crucial for proliferation and survival. Consequently,
efforts have recently increased to identify the precise role
of Epo-EpoR in a variety of cell types. This allowed identification
of physiologically relevant targets that led to original therapeutic
strategies.
[Back to top]
Determinants of Perceived Severity of Hypertension and Drug-Compliance
in Hypertensive Patients
Arie Dijkstra, Vanessa Okken, Menco Niemeijer
and Ton Cleophas
Background:Severity of illness is not an important
determinant of drug-compliance. In this paper we hypothesize
that the perceived severity of illness rather than
the true severity of illness is a determinant of
drug-compliance. If this is true, then it will be worthwhile
for physicians to look for factors determining this perceived
severity of illness.
Objectives: (I) To test in a prospective survey whether
this hypothesis can be confirmed in mildly hypertensive patients,
and (II) to identify factors determining their perceived severity
of illness.
Methods: 450 patients were invited to participate
in a prospective survey if their systolic blood pressure had
been between 140 and 170 mm Hg and their diastolic blood pressure
between 90 and 100 mm Hg despite treatment, for at least three
clinic visits. Based on previously published data three factors
possibly contributing to the perceived severity of hypertension
were identified: (1) objective medical information, (2) expected
physical symptoms, and (3) a positive social identification
with fellow-patients. These factors were used as independent
determinants in a multiple linear regression model with perceived
severity of hypertension as outcome variable. Subsequently,
this outcome variable together with patient characteristics
was used as an independent variable in a multiple logistic
regression model with drug-compliance as outcome variable.
Results: 176 patients, mean age 62 years, 52% females,
completed the study. In the multiple linear regression analysis
all of the three identified factors were statistically significant
predictors of the perceived severity of hypertension with
beta-values from 0.22 to 0.26, and p-values between 0.031
and 0.004. The multiple logistic regression analysis demonstrated
that, after adjustment for gender, age, school, and general
health status, the perceived severity of hypertension was
a significant determinant of drug-compliance at p = 0.040.
Discussion: The present study shows what information
patients use to conclude on the level of their blood pressure
being too high or not. This information can be used to better
understand the patients’ ideas about health and possibly
to influence these ideas. Patients’ conclusion about
the level of their blood pressure predicted their drug-compliance.
Our study increased insight into the psychology of the patient
and the results may be helpful to physicians in order to further
understand and influence patient behaviors, particularly,
adherence to antihypertensive medication.
[Back to top]
Endothelial Progenitors in Vascular Repair and Angiogenesis:
How Many are Needed and What to do?
Carla Real, Francisco Caiado and Sergio
Dias
Defects in the regulation of neo blood vessel
growth (angiogenesis) or in vessel repair are major complications
in many diseases, such as cancer, diabetes, atherosclerosis
and myocardial infarction.
In these diseases it was shown that the number of circulating
endothelial progenitor cells (EPC) was altered. This has been
associated with the angiogenic status and patient prognosis.
However, the regulation of angiogenesis depends not only on
the number of circulating EPC but also on their functions.
EPC are bone marrow derived cells that are recruited into
the peripheral blood in situations of vascular repair/angiogenesis
or vascular stress. EPC are believed to exert their function
using mainly two strategies: activating locally the endothelial
cells and/or differentiating into mature endothelial cells
that integrate the damaged vessels. To do this, EPC must home
to “angiogenic active” sites, adhere to the activated/damaged
endothelial cells or to the extracellular matrix and participate
in the endothelial activation/repair process.
In vitro and in vivo experiments using animal
models revealed the importance of various signalling pathways
in these processes and, in patients, new therapeutic strategies
are being developed based on the specific functions of EPC.
Although the role of EPC in vessel repair in disease is not
totally understood, it becomes clear that the activation state
of these cells is critical for the vessel repair process.
Our previous work generated a detailed gene expression profile
of EPC during the endothelial differentiation process in
vitro. With this information, it has been possible to
identify numerous molecular targets crucial for EPC differentiation
and function and to test their involvement in EPC function
during wound healing or tumor angiogenesis.
The importance of EPC identification, activation state and
function in vascular repair and in angiogenesis in disease
will be discussed in this review.
[Back to top]
Soluble CD40L and its Role in Essential Hypertension: Diagnostic
and Therapeutic Implications
Patrizia Ferroni and Fiorella Guadagni
Soluble CD40 ligand (sCD40L) is involved in the pathogenesis
of risk factor-related vascular damage and has been regarded
as a molecular link between inflammation, thrombosis and angiogenesis.
Given the increasingly recognized theory that hypertension
is in part an inflammatory disorder, the contribution of CD40/CD40L
dyad is becoming one of the outstanding puzzles in the pathophysiology
of hypertension. CD40/CD40L signaling appears, in fact, like
a versatile pathway that vehicles information within vascular
cells. Several distinct lines of investigation in the context
of hypertension dealing with low-grade inflammation are now
merging, with CD40/CD40L system as the missing link. As an
example, recent data suggest that the vasoactive peptide angiotensin
II promotes and augments the inflammatory activation induced
by CD40/CD40L ligation in human vascular cells. Accordingly,
sCD40L levels are elevated in hypertensive patients and might
discriminate hypertensive patients at a high risk of cardiovascular
events. This review will summarize the present understanding
of the contribution of sCD40L to inflammation, thrombosis
and neoangiogenesis in hypertension. Furthermore, given the
well established effects that antihypertensive drugs exert
on the vasculature beyond blood pressure lowering (pleiotropic
effects), we will also discuss the effects of antihypertensive
treatment on these phenomena.
[Back to top]
Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX
1), a Relevant Target for Diabetic Vasculopathy?
Geneviève Renie
Mechanisms through which major risk factors accelerate
diabetic angiopathy include low density lipoprotein (LDL)
oxidation and advanced glycation end products (AGEs) formation.
Lectin-like oxidized LDL receptor (LOX-1) is a newly identified
vascular receptor for oxidized LDL (oxLDL) and AGEs. LOX-1
is up-regulated in vascular endothelium of diabetic animals
and thus may be relevant to the development and progression
of human diabetic vasculopathy. The mechanisms responsible
for LOX-1 induction in diabetes remain unclear but appear
to involve metabolic and inflammatory stimuli relevant to
diabetes. Such factors may impact on LOX-1-mediated pro-atherogenic
events, including endothelial dysfunction and plaque destabilization.
Previous studies have shown that drugs commonly used in the
treatment of type 2 diabetic patients, including statins and
antidiabetic agents, inhibit endothelial LOX-1 expression.
This review summarizes recent advances related to the role
of LOX-1 in macrovascular diseases, its regulation by some
derangements commonly found in diabetic patients and its modulation
by vasculoprotective drugs.
[Back to top]
A More Accurate Approach to Molecular Genetics Analysis in
Vascular Disease
Jose Ignacio Lao Villadóniga
Vascular disease (VD) and its complications
are the leading cause of morbility and death in modern civilisations.
Primary VD is a very complex and multifactorial process which
is still not well understood. Recent studies provide clear
and convincing evidences that genetic risk factors (gene polymorphisms)
contribute significantly to the pathogenesis and expression
of VD. Thus, we have to analyse the interaction of multiple
polymorphisms in multiple genes coding for several proteins
involved in the molecular etiopathogenesis of VD. All these
polymorphisms are interacting among them, enhancing or antagonizing
their pathogenic effects, and at the same time, their final
phenotypic expression is constantly modulated by other non-genetic
factors (environmental and behavioural). Thus, gene-environment
interaction analysis would be crucial for the correct etiopathogenic
evaluation.
According to a particular assortment of positive and negative
gene variants (alleles) present in their genetic pool some
individuals develop VD without manifesting very extreme levels
of any of the classical risk factors while other individuals
remain free of disease despite exposure to several risk factors.
Taking into account that this heterogeneity is due to their
different genetic susceptibility it is necessary to make an
analyse in deep including all genetic polymorphisms which
have been involved in the vascular etiopathogenesis in order
to design the most appropriate intervention strategy.
Using a more accurate genetic polymorphism analysis it would
be possible to predict complications in order to make prevention
designing an individualized drug therapy on the basis of a
person’s genetic makeup. However, an accurate genetic
testing is not being used as often as it is expected because
there are so many polymorphisms to consider and DNA tests
available to analyse them are usually dispersed throughout
different laboratories because they are not included in an
unified protocol. In this sense, DNA-Chip technology used
as susceptibility (predisposition) testing has evolved into
a powerful tool providing informative data from multiple loci
in complex diseases like VD (where multiple genetic alterations
contribute, but each on a small scale). This technology could
greatly reduce health care costs by reducing the number of
useless diagnostic tests making possible the genetic dissection
of complex human diseases.
The proposed paper will discuss these topics with special
emphasis on how genetic polymorphisms influence in the individual
susceptibility to develop vascular disease and its complications
as well as the way that may affect individual responses to
several drugs used in the VD management.
[Back to top]
Adipose Tissue: The Link Between Obesity and Cardiovascular
Disease
Vanessa DeClercq, Carla Taylor and
Peter Zahradka
The ever-increasing prevalence of cardiovascular disease (CVD)
associated with obesity is linked through signaling pathways
within adipose tissue. Adipose tissue functions as an endocrine
organ, producing and secreting a variety of bioactive molecules.
In obesity, the adipose tissue itself undergoes changes in
cell size which alters its normal physiological function.
Altered adipocyte function changes production and secretion
of adipokines, such as leptin, adiponectin, angiotensinogen,
plasminogen activator inhibitor-1, resistin, and several inflammatory
molecules. Adipokines interact with other tissues and cells
in the body, including many pathways linked to CVD. Future
research in the area of obesity-related CVD requires further
investigation into a combination of lifestyle and pharmacological
therapies that alter adipokine production by reducing adipocyte
size.
|
