Cardiovascular
& Hematological Agents in Medicinal Chemistry
ISSN: 1871-5257
Cardiovascular & Hematological
Agents in Medicinal Chemistry
Volume 4, Number 3, July 2006
Contents
Cytokines and Hormones in the Regulation of Hypoxia
Inducible Factor-1α
(HIF-1α)
Pp. 189-197
J. Zhou and B. Brüne
[Abstract]
Expression and Functions of Vasoactive Substances
Regulated by Hypoxia-Inducible Factor-1 in Chronic Hypoxemia
Pp. 199-218
G.L. Tipoe, T.Y.-H. Lau, A.A. Nanji and M.-L. Fung
[Abstract]
Blockade of the Renin-Angiotensin-Aldosterone System:
Effects on Hypertensive Target Organ Damage Pp. 219-228
A.M. Grandi and A.M. Maresca
[Abstract]
Interleukin-1 and Occlusive Arterial Diseases
Pp. 229-235
M. Kusuhara, K. Isoda and F. Ohsuzu
[Abstract]
Antiplatelet and Antileukocyte Effects of Cardiovascular,
Immunomodulatory and Chemotherapeutic Drugs Pp. 237-261
R. Nosal
[Abstract]
Dietary Fat and Hypertension: A Novel Approach Through
the Proteolytic Regulatory Enzymes of the Renin-Angiotensin-System
Pp. 263-276
J.M. Martínez-Martos and M.J. Ramírez-Expósito
[Abstract]
Abstracts
[Back to top]
Cytokines and Hormones in the Regulation of Hypoxia
Inducible Factor-1α
(HIF-1α)
J. Zhou and B. Brüne
Hypoxia inducible factor-1 (HIF-1) is a central component
of the oxygen sensing system that coordinates cellular responses
to conditions of decreased oxygen availability. The hypoxia
inducible transcription factor HIF-1 is a heterodimer composed
of the helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) proteins HIF-1alpha
and the aryl hydrocarbon nuclear translocator (ARNT) also
known as HIF-1beta. Transactivation of HIF-1 transmits a hypoxic
signal into patho-physiological responses such as angiogenesis,
erythropoiesis, vasomotor control, an altered energy metabolism,
as well as cell survival decisions by regulating a staidly
growing number of target genes. Among recent advances are
the discoveries that cytokines and growth factors make use
of the 'hypoxic signaling system' under normoxia. Here we
summarize current knowledge and existing concepts that help
to understand how cytokines and hormones affect protein accumulation
of HIF-1alpha and discuss potential implications of activating
HIF-1 under normoxia. Considering the fundamental role of
cytokines during inflammation may predict a role of HIF-1alpha
in coordinating cellular responses to pathogens and point
to the connection of cancer and inflammation. Moreover, we
will address potential feed-back mechanisms showing an impact
of HIF-1 on cytokine production. These considerations suggest
an intimate signaling cross-talk between cytokines and the
HIF-1 system.
[Back to top]
Expression and Functions of Vasoactive Substances
Regulated by Hypoxia-Inducible Factor-1 in Chronic Hypoxemia
G.L. Tipoe, T.Y.-H. Lau, A.A. Nanji and M.-L. Fung
The aims of the present review are to summarize and to
discuss the role of hypoxia-inducible factor-1 (HIF-1) and
the expression and functions of vasoactive substances in chronic
hypoxemia with specific focus in the liver and the carotid
body. Vascular remodelling and vasoactive substances play
important functional roles in the adaptive response to chronic
hypoxemia for the maintenance of oxygen homeostasis in all
systems in man. HIF-1 regulates the gene expression of vasoactive
substances such as vascular endothelial growth factor (VEGF),
endothelin-1 (ET-1) and enzymes for producing nitric oxide
(NO). Recent studies have shown the effect of chronic hypoxia
on the expression of HIF-1α
and HIF-1-target genes in multiple organ systems including
the liver and the carotid body. Results are consistent with
increases in the hematocrit levels, pulmonary arterial pressure
and right heart mass developed during chronic hypoxia. In
addition, the carotid body is also hyperplastic and increases
in organ mass with increased levels of HIF-1α
and the vasoactive substances. These molecules increase the
mitotic activity and modulate the excitability of the chemoreceptor.
Intriguingly, the liver morphology, serum alanine aminotransferase
and 8-isoprostane levels are within normal range in chronic
hypoxia, suggesting the absence of significant oxidative stress.
Yet, the HIF-1α
is upregulated and the mRNA and protein levels of VEGF, ET-1,
inducible and constitutive NO synthases are elevated in the
liver during chronic hypoxia. In conclusion, the adaptive
response to long-term hypoxemia involves compensatory mechanisms
mediated by expressing significant levels of HIF-1α
and vasoactive substances regulated by HIF-1.
[Back to top]
Blockade of the Renin-Angiotensin-Aldosterone
System: Effects on Hypertensive Target Organ Damage
A.M. Grandi and A.M. Maresca
The renin-angiotensin-aldosterone system (RAAS) plays
a relevant role not only in the pathophysiology of essential
hypertension, but also in the development of hypertensive
target organ damage. Different drugs acting on RAAS components
are now available: angiotensin-converting-enzyme (ACE) inhibitors,
angiotensin II AT1 receptors blockers (ARBs), non-selective
and selective aldosterone antagonists. The review will focus
on their effects on hypertensive organ damage. In fact, apart
from the well known efficacy in reducing blood pressure, all
these drugs have been demonstrated to protect against target
organ damage, reversing or preventing its development. The
main issues addressed will be: effects of the RAAS blockade
on heart and kidney disease, protective action against arterial
wall damage, with a focus on the endothelial protection. The
comparison among ACE inhibitors, ARBs and aldosterone antagonists
will be discussed, with specific reference to different class
and/or drug effects and to the results of few studies evaluating
the effects of combination therapy with different drugs blocking
the RAAS.
[Back to top]
Interleukin-1 and Occlusive Arterial Diseases
M. Kusuhara, K. Isoda and F. Ohsuzu
Interleukin (IL)-1 is a pro-inflammatory cytokine and
a central mediator in the cytokine network, and is known to
control important functions both in the immune system and
inflammation. The activity of IL-1 is counter-regulated by
its endogenous inhibitor, IL-1 receptor antagonist (IL-1Ra).
IL-1 and IL-1Ra are produced and secreted by a variety of
cells including those responsible for controlling immunity.
A recent study indicated that IL-1 and IL-1Ra transcripts
were expressed in the vessel wall, suggesting that these cytokines
contribute to the development and progression of vascular
diseases.
In this review, we will discuss the recent advances in our
understanding of the mechanism of action of IL-1 in occlusive
arterial diseases such as neointimal hyperplasia and atherosclerosis,
specifically in a mouse model.
[Back to top]
Antiplatelet and Antileukocyte Effects of Cardiovascular,
Immunomodulatory and Chemotherapeutic Drugs
R. Nosal
In vitro and ex vivo interactions of betaadrenoceptor
blocking drugs, antihistamines and chloroquine with blood
platelets and polymorphonuclear leukocytes resulted in different
alterations of regulatory functions of these blood cells.
Inhibition of platelet aggregation, arachidonate regulatory
pathway, 5-hydroxytryptamine transportation, removal of platelet
membrane receptors, inhibition of second messenger pathways
at subcellular level and suppression of phagocytosis are indicative
of nonreceptor rather than specific receptor interactions.
Binding of drugs with biomembranes is reversible depending
on the ionic charge of the molecule and hydrophobicity of
the bilayer, partition coefficient, pH and pKa
of the amphiphilic molecules and other physico-chemical properties
of amphiphilic drugs. Alterations in the drug molecule structure
alters the drug-phospholipid binding profile. Any change in
the metabolism of membrane phospholipids directly or indirectly
influences one or more of the important components of the
phospholipid-signalling pathway. In addition to changes in
phospholipase A, C and D activities, protein kinase C, calmodulin-phosphodiesterase,
Ca2+
,Mg2+-ATPase,
Na+,K+-ATPase
and other messengers were found to be changed in cells and
tissue after cationic amphiphilic drug (CAD) administration.
Although not much has been understood of the mechanism by
which some CAD affect immune functions, there are good reasons
to suggest that these effects might occur.
CADs share sufficient similarities in their structure even
though they come from diverse pharmacological classes. CADs
affect ion transport, immune functions, tumour growth, serotonin
metabolism and several other functions in the body. Extensive
therapeutic use and associated side effects have generated
a great deal of interest in understanding the nonreceptor
interactions with CADs.
[Back to top]
Dietary Fat and Hypertension: A Novel Approach
Through the Proteolytic Regulatory Enzymes of the Renin-Angiotensin-System
J.M. Martínez-Martos and M.J. Ramírez-Expósito
The role of individual fatty acids in blood pressure
regulation is unclear, although it is known that the modifications
in the levels of fatty acids in the diet are able to change
the entire profile of fatty acids as well as cholesterol levels
in cellular membranes. These chemical changes are accompanied
by changes in the physiological state of the cellular membranes
and have suggested an influence on cellular metabolism and
of course, on the regulatory processes. Local and circulating
renin-angiotensin-systems (RAS) are examples of systems that
may be involved in the pathogenesis of hypertension. Angiotensin
II (AngII) has been considered as the main effector peptide
of the RAS, but other peptides derived from the metabolism
of AngII, as angiotensin III (AngIII) and angiotensin IV (AngIV)
have shown to play significant roles. This review will briefly
summarize what is known about the effects of fatty acids,
cholesterol and other related compounds on the activity of
the aminopeptidases involved in the metabolism of Ang II and
AngIII. We conclude that these enzyme activities may be modified
in different way, and therefore, possible modifications in
RAS and in cardiovascular illness may be possible too.
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