Cardiovascular
& Hematological Disorders - Drug Targets
ISSN: 1871-529X
Current Drug Targets - Cardiovascular
& Hematological Disorders
Volume 6, Number 1, March 2006
Contents
Reactive Oxygen Species in Vascular Wall
Pp. 1-19
L.M. Yung, F.P. Leung, X. Yao, Z.-Y. Chen and Y. Huang
[Abstract]
Processing of Amyloid Precursor Protein as a Biochemical
Link Between Atherosclerosis and Alzheimer’s Disease
Pp. 21-34
D.M. Jans, W. Martinet, T.J.L. Van De Parre,
A.G. Herman, H. Bult, M.M. Kockx and G.R.Y. De Meyer
[Abstract]
The Use of Carvedilol in Pediatric Heart Failure
Pp. 35-42
S.C. Greenway and L.N. Benson
[Abstract]
The Antiplatelet Drug Target in Atherosclerotic
Diseases Pp. 43-55
P.R. Belcher, A.J. Drake-Holland and M.I.M. Noble
[Abstract]
The Relationship Between Hypertensive Retinopathy
and
Angiotensin Converting Enzyme Gene Polymorphism Pp.
57-61
Nezihi Baris, Bahri Akdeniz, Filiz Ozerkan, Remzi
M. Onder,
Ulus Akarca and Sema Guneri
[Abstract]
Hypertension and Counter-Hypertension Mechanisms
in
Giraffes Pp. 63-67
Q.G. Zhang
[Abstract]
Erratum Pp. 69
Abstracts
[Back to top]
Reactive Oxygen Species in Vascular Wall
L.M. Yung, F.P. Leung, X. Yao, Z.-Y. Chen and Y. Huang
Reactive oxygen species (ROS) contribute to the pathogenesis
of cardiovascular diseases including hypertension, atherosclerosis,
cardiac hypertrophy, heart failure and diabetes mellitus.
Oxidative stress is resulted from excessive generation of
ROS that outstrips the antioxidant system. Various agonists,
pathological conditions and therapeutic interventions lead
to modulated expression and function of oxidant and antioxidant
enzymes, including NAD(P)H oxidase, endothelial nitric oxide
synthase, xanthine oxidase, myeloperoxidase, superoxide dismutases,
catalase and glutathione peroxidase. ROS formed in vascular
wall target a wide range of signaling molecules and cellular
pathways in both endothelium and vascular smooth muscle, such
as transcription factors, protein tyrosine phosphatase, protein
tyrosine kinase, mitogen-activated protein kinase, Ca2+
transporting system and protein modification.
ROS also have distinct physiological and pathophysiological
impacts on vascular cells. ROS contribute to vascular dysfunction
and remodeling through oxidative damage by (1) reducing the
bioavailability of NO, (2) impairing endothelium-dependent
vasodilatation and endothelial cell growth, (3) causing apoptosis
or anoikis, (4) stimulating endothelial cell migration, and
(5) activating adhesion molecules and inflammatory reaction,
leading to endothelial dysfunction, an initial episode progressing
toward hypertension and atherosclerosis. Cellular events underlying
these processes involve changes in vascular smooth muscle
cell growth, apoptosis/anoikis, cell migration, inflammation,
and vasoconstriction. The present communication focuses on
the biology of ROS signaling in vascular cells, discusses
how oxidative stress contributes to vascular damage, and the
therapeutic strategies/biotic factors that can prevent or
treat ROS-associated cardiovascular disorders.
[Back to top]
Processing of Amyloid Precursor Protein as a Biochemical
Link Between Atherosclerosis and Alzheimer’s Disease
D.M. Jans, W. Martinet, T.J.L. Van De Parre,
A.G. Herman, H. Bult, M.M. Kockx and G.R.Y. De Meyer
Macrophage activation in atherosclerotic plaques plays a
role in plaque destabilization, rupture and subsequent atherothrombosis.
Platelet phagocytosis that occurs within human atherosclerotic
plaques can activate macrophages and it has been suggested
that the platelet constituent amyloid precursor protein (APP)
is involved. Recent studies show that amyloid β
(Aβ),
a peptide extensively studied in Alzheimer’s disease
and that is cleaved from APP by β-
and γ -secretase,
and/or Aβ-like
peptides are also present in human atherosclerotic plaques,
in particular in activated, inducible nitric oxide synthase
(iNOS) expressing perivascular macrophages that had phagocytized
platelets. In vitro studies confirm that platelet
phagocytosis leads to macrophage activation and suggest that
platelet-derived APP is proteolytically processed to Aβ-like
peptides, resulting in iNOS induction. In addition, non-steroidal
anti-inflammatory drugs (NSAIDs) and HMG-CoA reductase inhibitors
(statins), two classes of drugs reported to affect APP processing
and Aβ
formation in Alzheimer’s disease, have been evaluated
for their capacity to inhibit macrophage activation evoked
by platelet phagocytosis. Remarkably, the same NSAIDs reported
to alter γ
-secretase activity in Alzheimer’s disease also
reduce macrophage activation after platelet phagocytosis and
inhibit formation of Aβ-containing
peptides. From the statins investigated (fluvastatin, atorvastatin,
simvastatin, pravastatin, lovastatin and rosuvastatin) only
fluvastatin and atorvastatin selectively inhibit macrophage
activation after platelet phagocytosis, possibly through inhibition
of Rho activity. Taken together, these new findings point
to the involvement of platelet-derived APP in macrophage activation
in atherosclerosis and suggest a biochemical link between
atherosclerosis and Alzheimer’s disease. Accordingly,
drugs interfering with APP processing might have an impact
on both diseases.
[Back to top]
The Use of Carvedilol in Pediatric Heart Failure
S.C. Greenway and L.N. Benson
Chronic congestive heart failure has become a significant
medical burden in the adult and a growing problem in the pediatric
age group. While the etiologies of heart failure differ between
children and adults, applied medical therapies are generally
the same. In this regard, over the last decade, β
-adrenergic receptor blockade has become an important
component in drug therapy of congestive heart failure in the
adult population. A third-generation β
-blocker, carvedilol, has now been shown in adult trials
to be efficacious in the treatment of heart failure and has
been shown to be superior to other similarly used β
-blockers. Carvedilol use has been adapted into pediatric
heart failure practice although data supporting its efficacy
in infants and children are scarce. This review will describe
the application of carvedilol in the adult, as it pertains
to pediatric practice, review the existing pediatric literature
and describe our institution’s experience with carvedilol
in heart failure therapy.
[Back to top]
The Antiplatelet Drug Target in Atherosclerotic Diseases
P.R. Belcher, A.J. Drake-Holland and M.I.M. Noble
The aim of this review is (1) to give a rationale for anti-platelet
therapy based on mechanisms of platelet rich arterial thrmbosis,
(2) to point out the pitfalls involved in monitoring therapy
with platelet function tests and (3) to outline the potential
clinical applications of such therapy based on the various
modes of action of anti-platelet drugs. The primary event
in arterial thrombosis is platelet-mediated, either due to
increased shear or exposed collagen, followed by fibrin-rich
thrombosis. Anti-platelet therapy needs to be monitored but
most platelet function tests, now in use, do not reflect in
vivo function; the anticoagulant used for blood samples
removes extra-cellular calcium ions, platelets are often separated
before the test, or very high doses of agonist are used: all
of these can give misleading results. We review means whereby
platelet function can be monitored in whole blood samples
anticoagulated with the pure thrombin inhibitor, hirudin.
We review the available methods of modifying platelet activity
and are particularly interested in agents that do not cause
bleeding. Present therapy causes bleeding by interference
with COX1, the P2Y12 receptor or the platelet fibrinogen
receptor complex, all of which can be associated with bleeding
complications. In contrast, serotonin does not influence formation
of haemostatic layers although it is implicated in shear-induced
aggregation and thrombus propagation by positive feedback
from the large amount of intraplatelet serotonin.
We suggest that further investigation of selective serotonin
5HT2 antagonism would allow effective management
of intravascular thrombosis without bleeding complications.
This would be safer both as prophylaxis and would also allow
cardioprotection of vascular patients undergoing surgical
operations.
[Back to top]
The Relationship Between Hypertensive Retinopathy
and
Angiotensin Converting Enzyme Gene Polymorphism
Nezihi Baris, Bahri Akdeniz, Filiz Ozerkan, Remzi
M. Onder,
Ulus Akarca and Sema Guneri
Objective: Hypertensive retinopathy is an important complication
and a major site of target organ damage from hypertension.
Angiotensin converting enzyme (ACE) has a main role in cardiovascular
physiology. It was shown that ACE gene polymorphism is related
to plasma concentrations of ACE. We aimed to investigate the
relationship between ACE gene polymorphism and hypertensive
retinopathy.
Methods: One-hundred and eight patients (62 female, mean age;
52.8 ± 7.0 years) with essential hypertension and 30
healthy volunteers were enrolled in this study. Hypertensive
retinopathy was diagnosed in a dark room with direct ophthalmoscopy
by a single ophthalmologist who was blinded to clinical data.
Polymerase chain reaction analysis was used to detect the
insertion/deletion (l/D) polymorphism of the ACE gene. Patients
were assigned to Group DD, Group ID and Group II. Three genotypic
subgroups were compared for hypertensive retinopathy.
Results: There were 42 patients (27 female, mean age: 52.4
± 7.8) in DD group; 51 patients (28 female, mean age:
53.6 ± 6.9) in ID group and 15 patients (7 female,
mean age: 51.2 ± 5.6) in II group. Basal characteristics
of the patients were similar in the three groups. The genotypic
distributions of patients and healthy controls were comparable.
Hypertensive retinopathy was determined in 15 (35.7%) patients
in DD group, 8 (15.6%) patients in ID group and 2 (13.3%)
patients in II group (p<0.05).
Conclusion: We found a significant relationship between ACE
gene I/D polymorphism and hypertensive retinopathy. Identification
of ACE genotype in hypertensive patients might be useful to
discriminate the patients who are more susceptible to hypertensive
retinopathy.
[Back to top]
Hypertension and Counter-Hypertension Mechanisms in
Giraffes
Q.G. Zhang
The giraffe is unique as its head is 2500-3000 millimeters
above its heart, thus the giraffe’s heart must pump
hard enough to overcome the huge hydrostatic pressure generated
by the tall column of blood in its neck in order to provide
its head with sufficient nutrients and oxygen. Giraffes therefore
have exceptionally high blood pressure (hypertension) by human
standards. Interestingly, the “unnaturally” high
blood pressure in giraffes does not culminate in severe vascular
lesions, nor does it lead to heart and kidney failure, whereas
in humans, the same blood pressure is exceedingly dangerous
and will cause severe vascular damage. Intrinsically, natural
selection likely has provided an important protective mechanism,
because hypertension develops as soon as the giraffe stands
up and erects its neck immediately after birth. Therefore,
those individual giraffes who did not tolerate the burden
of hypertension presumably developed acute heart failure and
renal failure, not surviving to reproductive age. The genes
and genotypes of animals that did not survive are thus predicted
to have been gradually eliminated from the gene pool by natural
selection. By the same process, genes that protect against
hypertensive damage would be preserved and inherited from
generation to generation. Some unique ingredients of the giraffe’s
diet may also provide an extrinsic mechanism for the prevention
of hypertension and the prevention of fatal end-stage organ
damage. The fascinating nature of the protective mechanisms
in giraffes may provide a conceptual framework for further
experimental investigations into mechanisms as well as prevention
and treatment of human hypertension and cardiovascular disease.
|
