|
Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 5, Number 1, January 2007
Contents
Pharmacologic Modulators of Soluble Guanylate
Cyclase/Cyclic Guanosine Monophosphate in the Vascular System
- From Bench Top to Bedside Pp. 1-14
Elias B. Jackson, Jr., Somnath Mukhopadhyay and David
A. Tulis
[Abstract] [Full
text article]
Use of BNP and CRP as Biomarkers in Assessing Cardiovascular
Disease: Diagnosis Versus Risk Pp. 15-25
Virginia M. Miller, Margaret M. Redfield and Joseph P.
McConnell
[Abstract] [Full
text article]
Do Adult Stem Cells Ameliorate the Damaged Myocardium?
Human Cord Blood a Potential Source of Stem Cells
Pp. 27-44
Furfaro, Elise M.K.; Gaballa, Mohamed A.
[Abstract] [Full
text article]
Endothelin-1-Induced Signaling Pathways in Vascular
Smooth Muscle Cells Pp. 45-52
Ali Bouallegue, Grace Bou Daou and Ashok K. Srivastava
[Abstract] [Full
text article]
Optical Techniques in the Assessment of Peripheral
Arterial Disease Pp. 53-59
Mohamad E. Alnaeb, Nasser Alobaid, Alexander M. Seifalian,
Dimitri P. Mikhailidis and George Hamilton
[Abstract] [Full
text article]
Vascular Disease: A New Progenitor Biology
Pp. 61-68
Pat Metharom and Noel M. Caplice
[Abstract] [Full
text article]
Equilibrative Nucleoside (ENTs) and Cationic Amino
Acid (CATs) Transporters: Implications in Foetal Endothelial
Dysfunction in Human Pregnancy Diseases Pp. 69-84
Paola Casanello, Carlos Escudero and Luis Sobrevia
[Abstract] [Full
text article]
The Significance of Endothelium-Derived Hyperpolarizing
Factor in the Human Circulation Pp. 85-92
Qin Yang, Anthony P.C. Yim and Guo-Wei He
[Abstract] [Full
text article]
Abstracts
[Back to top]
Pharmacologic Modulators of Soluble Guanylate Cyclase/Cyclic
Guanosine Monophosphate in the Vascular System - From Bench
Top to Bedside
Elias B. Jackson, Jr., Somnath Mukhopadhyay and David
A. Tulis
[Full
text article]
Guanosine-dependent cyclic nucleotide second messenger signaling
has been implicated as a pivotal mediator of vascular function
under both homeostatic eutrophic conditions as well as in
the inimical environs of injury and/or disease. This biological
system is highly regulated through reciprocal, complimentary,
and often redundant upstream and downstream molecular and
cellular elements and feedback controls. Key endogenous factors
of the guanosine-dependent cyclic nucleotide cascade include
upstream gaseous activating ligands (nitric oxide, carbon
monoxide), downstream substrates (cGMP-gated ion channels,
cGMP-dependent protein kinases), and cGMP hydrolyzing phosphodiesterases.
This intricate system also has capacity to “cross-talk”
with parallel adenosine-dependent cyclic nucleotide machinery.
Numerous complexes of ligands, enzymes, cofactors, and substrates
present significant targets for pharmacologic modulation at
the cellular, genetic, and/or molecular level eventuating
therapeutically as constructive functional responses observed
in vascular physiology and/or pathophysiology. Interestingly,
emerging evidence based largely on transgenic mouse models
challenges the historically accepted concept that this signaling
system functions principally as a therapeutic modality in
cardiac and vascular tissues.
The general purpose of this update is to provide current information
on recently described neoteric agents that impact multifaceted
and critical cGMP-dependent signaling in the vascular system.
Emphasis will be placed on novel agents that exert significant
and often multiple actions on upstream and downstream sites
and are capable of eliciting robust effects on guanosine-dependent
cellular actions. Individual sections will be devoted to agents
that rely on an intact and functional cyclase heme and those
that operate independently of the sGC heme. Attention will
be placed on the physiologic and pathophysiologic clinical
manifestations of these pharmacologic regimens. This review
will conclude with some thoughts for future directions for
study and continued discovery of novel sGC/cGMP controllers
in the vascular system at the basic science and clinical levels.
[Back to top]
Use of BNP and CRP as Biomarkers in Assessing Cardiovascular
Disease: Diagnosis Versus Risk
Virginia M. Miller, Margaret M. Redfield and Joseph P.
McConnell
[Full
text article]
Biomarkers are used in medicine to facilitate diagnosis, assess
risk, direct therapy and determine efficacy of treatment.
Sensitivity and specificity are essential in order for a biomarker
to be useful. Brain natriuretic peptide (BNP) and C-reactive
protein (CRP) are considered biomarkers of cardiovascular
disease. However, they differ in function, sensitivity and
specificity. BNP is released from the myocardium in response
to myocardial stretch, a clear cause and effect relationship;
therefore, it is useful in the diagnosis of heart failure
when patients present with dyspnea of unknown origin and to
assess treatment in high risk patients with diagnosed heart
failure. Sex and age based reference ranges and partition
values are established from clinical trials and from populations
screened for the absence of cardiovascular disease. Highly
sensitive and reproducible methods are also available to measure
CRP. However, although CRP is associated with adverse cardiovascular
events, unlike BNP, multiple stimuli increase production of
CRP. Therefore, elevation in CRP is not specific to cardiovascular
disease. Partition values for CRP and cardiovascular risk
based on epidemiological studies predict risk for populations
but may not always be useful when used alone to predict individual
risk or to direct therapy. Given the non-specific stimuli
which affect circulating concentrations of CRP, using CRP
to monitor treatment to reduce cardiovascular risk may provide
little benefit without understanding or targeting the underlying
causes for its elevation.
[Back to top]
Do Adult Stem Cells Ameliorate the Damaged Myocardium?
Human Cord Blood a Potential Source of Stem Cells
Furfaro, Elise M.K.; Gaballa, Mohamed A.
[Full
text article]
The heart does not mend itself after infarction. However,
stem cells may revolutionize heart disease treatment. A vast
and growing body of evidence indicates that cell-based strategies
have promising therapeutic potential. Recent clinical and
pre-clinical studies demonstrate varying degrees of improvement
in cardiac function using different adult stem cell types
such as bone marrow (BM)-derived progenitor cells and skeletal
myoblasts. However, the efficacy of cell therapy after myocardial
infarction (MI) is inconclusive and the cellular source with
the highest potential for regeneration is unclear. Clinically,
BM and skeletal muscle are the most commonly used sources
of autologous stem cells. One major pitfall of using autologous
stem cells is that the number of functional cells is generally
depleted in the elderly and chronically ill. Therefore, there
is an urgent need for a new source of adult stem cells. Human
umbilical cord blood (CB) is a candidate and appears to have
several key advantages. CB is a viable and practical source
of progenitor cells. The cells are naïve and what’s
more, CB contains a higher number of immature stem/progenitor
cells than BM.
We review recent clinical experience with adult stem cells
and explore the potential of CB as a source of cells for cardiac
repair following MI. We conclude that there is a conspicuous
absence of clinical studies utilizing CB-derived cells and
there is a pressing need for large randomized double-blinded
clinical trials to assess the overall efficacy of cell-based
therapy.
[Back to top]
Endothelin-1-Induced Signaling Pathways in Vascular
Smooth Muscle Cells
Ali Bouallegue, Grace Bou Daou and Ashok K. Srivastava
[Full
text article]
Endothelin-1 (ET-1), a vasoactive peptide, is believed to
contribute to the pathogenesis of vascular abnormalities such
as hypertension, atherosclerosis, hypertrophy and restenosis.
ET-1 elicits its biological effects through the activation
of two receptor subtypes, ET-A and ET-B that belong to a large
family of transmembrane guanine nucleotide-binding protein-coupled
receptors (GPCRs). ET-1 receptor activation results in the
stimulation of several signaling pathways including mitogen-activated
protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3-K)
and protein kinase B (PKB). An intermediary role of Ca2+/calmodulin-dependent
protein kinases (CaMK), protein kinase C (PKC) as well as
receptor and non-receptor protein tyrosine kinases in triggering
the activation of MAPK and PI3-K/PKB signaling in response
to ET-1 has been suggested. Activation of these pathways by
ET-1 is intimately linked with the regulation of cellular
hypertrophy, growth, proliferation and cell survival.
Here we provide an overview of these signaling pathways in
vascular smooth muscle cells (VSMCs) with an emphasis on their
potential role in vascular pathophysiology.
[Back to top]
Optical Techniques in the Assessment of Peripheral
Arterial Disease
Mohamad E. Alnaeb, Nasser Alobaid, Alexander M. Seifalian,
Dimitri P. Mikhailidis and George Hamilton
[Full
text article]
A variety of optical techniques have been developed over the
years for experimental use in vascular disease, mainly for
the assessment of lower limb peripheral arterial disease (PAD).
Optical techniques have several advantages over more traditional
experimental approaches. Photoplethysmograph (PPG) was one
of the earliest methods used for this purpose; PPG satisfies
many of the conditions for a non-invasive technique to estimate
skin blood flow using infrared light, not only for research
but also in clinical practice. PPG is a promising, safe and
easy-to-use tool for diagnosis and early screening of various
atherosclerotic pathologies and could be useful for regular
GP-assessment or even self-monitoring of PAD at home or during
individual physical exercises. This review discusses the application
of PPG in the assessment of PAD.
[Back to top]
Vascular Disease: A New Progenitor Biology
Pat Metharom and Noel M. Caplice
[Full
text article]
Vascular disease is primarily the result of atherosclerosis
which affects all layers of the adult vessel wall. Our understanding
of atherosclerosis has evolved over the past three decades;
from initial hypotheses based on lipid deposition and fibrocellular
proliferation within the intima of the vessel wall to a more
complex interplay between conventional risk factors, inflammation
and the immune system implicating pan-vascular biologic processes.
More recently circulating progenitor cells have been shown
to possess diverse differentiation capacity within the remodelling
vessel wall. Current investigation of atherosclerosis therefore
encompasses an expanding field of biological science; from
molecular genetics, classical vascular biology, and immunology
to stem cell biology and vasculogenesis. However, a decade
after their initial description, scientists still know little
about the proximate relationship between vascular progenitor
cells and atherosclerosis progression or stability. In recent
years, the discovery of progenitor cells of myeloid origin
has offered the exciting prospect of merging classical concepts
of myeloid cell biology in atherosclerosis with evolving concepts
of myeloid cell plasticity and endothelial / smooth muscle
cells differentiation within the injured vessel wall. In this
context, early stage atherosclerosis associated with vascular
injury may involve neovascularisation and re-endothelialisation
in which a significant contribution comes from bone marrow-derived
vascular progenitor cells. For this review, emphasis will
be on endothelial progenitor cells (EPC), smooth muscle progenitor
cells (SPC) and putative myeloid precursors.
[Back to top]
Equilibrative Nucleoside (ENTs) and Cationic Amino
Acid (CATs) Transporters: Implications in Foetal Endothelial
Dysfunction in Human Pregnancy Diseases
Paola Casanello, Carlos Escudero and Luis Sobrevia
[Full
text article]
Gestational diabetes (GD, characterized by abnormal D-glucose
metabolism), intrauterine growth restriction (IUGR, a disease
associated with reduced oxygen delivery (hypoxia) to the foetus),
and preeclampsia (PE, a pregnancy complication characterized
by high blood pressure, proteinuria and increased vascular
resistance), induce foetal endothelial dysfunction with implications
in adult life and increase the risk of vascular diseases.
Synthesis of nitric oxide (NO) and uptake of L-arginine (the
NO synthase (NOS) substrate) and adenosine (a vasoactive endogenous
nucleoside) by the umbilical vein endothelium is altered in
pregnancies with GD, IUGR or PE. Mechanisms underlying these
alterations include differential expression of equilibrative
nucleoside transporters (ENTs), cationic amino acid transporters
(CATs), and NOS. Modulation of ENTs, CATs, and NOS expression
and activity in endothelium involves protein kinase C (PKC),
mitogen-activated protein kinases p42 and p44 (p42/44mapk),
calcium, and phosphatidyl inositol 3 kinase (PI3k), among
others. Elevated extracellular D-glucose and hypoxia alter
human endothelial function. However, information regarding
the transcriptional modulation of ENTs, CATs, and NOS is limited.
This review focuses on the effect of transcriptional and post-transcriptional
regulatory mechanisms involved in the modulation of ENTs and
CATs, and NOS expression and activity, and the consequences
for foetal endothelial function in GD, IUGR and PE. The available
information will contribute to a better understanding of the
cell and molecular basis of the altered vascular endothelial
function in these pregnancy diseases and will emphasize the
key role of this type of epithelium in placental function
and the normal foetal development and growth.
[Back to top]
The Significance of Endothelium-Derived Hyperpolarizing
Factor in the Human Circulation
Qin Yang, Anthony P.C. Yim and Guo-Wei He
[Full
text article]
Although nitric oxide (NO) is recognized as the primary vasodilator
derived from vascular endothelium in regulating the vascular
tone, another factor, i.e. the endothelium-derived hyperpolarizing
factor (EDHF), has recently gained much attention and has
been demonstrated to participate in vasodilatation in various
blood vessels from different species, despite its unidentified
nature. Most of the studies were conducted in animals and
the knowledge of this factor in the human vasculature is relatively
limited.
This review attempts to address the relevance of EDHF-mediated
function in humans with the possible identity of EDHF and
mechanisms involved. We consider the human vasculature where
EDHF involvement has been documented including the systemic,
coronary, and visceral (gastrointestinal, renal and reproductive)
circulation. In these vascular systems, EDHF plays a role
under physiological conditions either as another mechanism
or as the “back-up” for NO. Furthermore, the contribution
of EDHF changes under certain physiological conditions, such
as ageing and pregnancy. In addition, altered EDHF function
has been suggested in various pathological conditions including
heart diseases, atherosclerosis, hypertension, diabetes, eclampsia,
glaucoma, chronic renal failure, erectile dysfunction and
ischemia-reperfusion period during open heart surgery.
Pharmacological agents such as potassium channel openers or
cytochrome P450 metabolites have been used to either protect
or recover EDHF-dependent mechanisms. To further develop new
therapeutic strategies that target EDHF, a better understanding
is essential with regard to the function of EDHF under pathophysiological
conditions in humans. Furthermore, the interaction between
NO and EDHF as well as their relative contributions in various
conditions are critical.
|
