|
Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 6, Number 6, October 2005
Contents
Editorial Pp.365
Functional Evolution of Tissue Factor, the Archetype
of the Cytokine Receptor Family Pp.367
C. Arnold Spek, Marieke van Zoelen, Sander H. Diks and
Maikel P. Peppelenbosch
[Abstract]
Emerging Insights in the Role of Tissue Factor
in Cancer Pp.375
Henri H. Versteeg
[Abstract]
Inherited Coagulation Factor VII and X Deficiencies
Associated with Severe Bleeding Diathesis: Molecular Genetics
and Pathophysiology Pp.383
Keren Borensztajn and C. Arnold Spek
[Abstract]
RNA-Based Gene Therapy for Haemophilia B
Pp.401
Maikel P. Peppelenbosch, Francesca Milano, Carmen V. Ferreira,
Anna Knapinska, Sander H. Diks and C. Arnold Spek
[Abstract]
Perspectives of Activated Protein C in the Vasculature:
Update on Proposed Roles of the Protein C Pathway Pp.405
S.H. Slofstra and H. Ten Cate
[Abstract]
Atherosclerosis and its Acute Consequences: Insights
from Genetic Association Studies Pp.411
S. Bezzina Wettinger and P.H. Reitsma
[Abstract]
Vascular Progenitor Cells in the Development of Transplant
Arteriopathy Pp.431
J.L. Hillebrands, H. Rienstra, G. Onuta and J. Rozing
[Abstract]
Blood Coagulation and the Risk of Atherothrombosis
Pp.439
Henri M.H. Spronk and Hugo Ten Cate
[Abstract]
Myocardial Ischemia and Reperfusion Injury: Studies
Using Transgenic and Knockout Mice Pp.449
W.M.C. Jong, H. Ten Cate, P.H. Reitsma and R.J. de Winter
[Abstract]
Coagulation and Cancer Therapy: The Potential of Natural
Compounds Pp.461
Giselle Z. Justo and Carmen V. Ferreira
[Abstract]
Molecular Mechanisms Regulating mRNA Stability: Physiological
and Pathological Significance Pp.471
Anna M. Knapinska, Patricia Irizarry-Barreto, Sri Adusumalli,
Ioannis Androulakis and Gary Brewer
[Abstract]
Using Microgravity for Defining Novel Anti-Atherosclerotic
Therapy Pp.487
Auke Verhaar, Kausilia K. Krishnadath and Maikel P. Peppelenbosch
[Abstract]
Abstracts
[Back to top]
Editorial
Upon vessel rupture, Tissue factor (TF) is the main initiator
of the coagulation cascade, normally not present on cells
that are in contact with the bloodstream, binds with high
affinity to the zymogen factor VII. The subsequent generation
of factor Xa, thrombin and fibrin deposition, finally results
in the formation of a blood clot. For decades it has been
thought that coagulation factors represent a group of relative
passive mediators involved in the linear transduction of the
coagulation cascade. Scientific progress in recent years has
taught us, however, that these factors actively engage target
cells to induce signal transduction and thus fulfil critical
functions in a wide variety of pathophysiological phenomena.
The most prominent example is the interaction between factor
VIIa and tissue factor, which is critical for neo- angiogenesis,
but also plays important roles in arteriosclerosis and inflammatory
processes. Importantly, various laboratories have now provided
convincing evidence that the effects of factor VIIa in pathophysiology
require the activation of other vitamin K-dependent coagulation
factors (especially factor X). In addition, also thrombin
is now generally accepted as a vitamin K-dependent coagulation
factor capable of inducing intracellular signal transduction.
In turn, this signalling plays an important role in cardiovascular
pathology as platelets from PAR4-deficient mice failed to
change shape, mobilize calcium, secrete ATP or aggregate in
response to thrombin. Many of the details of thrombin signal
transduction have now been elucidated by in vitro investigations
and especially feature prominent activation of Rho GTPases
and activation of p38 and p42/p44 MAP kinases, in turn important
for a variety of physiological events including angiogenesis,
and thus do not merit special attention. Hence in the present
issue we focus on more proximal events, models that bridge
this preclinical work to data with relevance for disease and
explore novel avenues for treating coagulation-related disease.
The importance of coagulation-factor-dependent signal transduction
in pathophysiology is clear. In addition, evidence is rapidly
emerging demonstrating an important role for protein C in
cardiovascular pathology (e.g. stroke and inflammation). Hence,
for proper understanding pathology associated with the coagulation
system knowledge of both evolutionary origin, RNA stabilization
of cytokines, and action function of TF, Factor VIIa and factor
X are essential and will be reviewed in this special issue
of current genomics by various authors. Together a pattern
emerges where, in general, vitamin K-dependent coagulation
factors provoke intracellular signal transduction The role
of the vitamin K-dependent coagulation factors in many cardiovascular
pathophysiological processes (e.g. myocardial infarction,
angiogenesis, and atherosclerosis) remains remarkably poorly
investigated, and although subject to review in this issue
will require a significant research effort in the future.
Hence, we would like to end this editorial with an appeal
to the appropriate authorities and funding agencies for continued
support to enable building on body of work described in this
special issue, resulting in improved patient care.
The authors wish to acknowledge the support from the Dutch
Heart foundation (grants 99.188 and 99.197) for the studies
presented in this special issue of current genomics.
Prof. Dr. Maikel P. Peppelenbosch
Editor
Cell Biology
University Medical Center Groningen
University of Groningen
A. Deusinglaan 1
9713 AV Groningen
The Netherlands
Tel: +31-50-3632522
Fax: +31-50-3632512
E-mail: m.peppelenbosch@med.umcg.nl
Dr. C. Arnold Spek
Co-Editor
Laboratory for Experimental Internal Medicine
Academic Medical Center
University of Amsterdam
Meibergdreef 9
1105 AZ Amsterdam
The Netherlands
Tel: +31-20-566 8750
Fax: +31-20-697 7192
E-mail: C.A.Spek@amc.uva.nl
[Back to top]
Functional Evolution of Tissue Factor, the Archetype
of the Cytokine Receptor Family
C. Arnold Spek, Marieke van Zoelen, Sander H. Diks and
Maikel P. Peppelenbosch
Already in the 19th century, it was accepted
that tissues display clot-promoting activity. The awareness
that a single protein was accountable for this pro-coagulant
effect led to the detection of tissue factor (tissue factor),
but for many years it was thought that tissue factor activity
was restricted to the activation of an auxiliary pathway that
had little biological significance. Today tissue factor is
recognised to be the primary biological initiator of the coagulation
cascade. In silico studies have highlighted the high
degree of structural similarity of tissue factor with the
super family of interferon receptors. The cytokine class II
receptor family has probably evolved from an ancient gene
coding for a pre-eukaryotic extracellular protein. Tissue
factor evolved from this protein and matching sequences are
found in invertebrates, especially insects. From tissue factor,
the other receptors evolved. Strikingly, the common evolutionary
origin of tissue factor and cytokine receptors is reflected
in identical signalling. The evolutionary origin of tissue
factor is the subject of the present review.
[Back to top]
Emerging Insights in the Role of Tissue Factor in
Cancer
Henri H. Versteeg
The principal initiator of coagulation, Tissue Factor (TF)
has now emerged as a critical key player in oncogenic events.
TF regulates tumor growth through processes such as anti-apoptosis,
tumor angiogenesis and metastasis in various solid tumors
such as colorectal carcinoma, glioma and breast tumors. In
the last few years it has become clear that these effects
are not, or partially, attributable to activation of coagulation.
Rather, activation of cellular receptors, by the binary TF:FVIIa
complex, the ternary TF:FVIIa:FXa complex or by thrombin,
results in intracellular signaling and altered cell behaviour.
In this review, the role of TF in complex with FVIIa or FVIIa:FXa
as well as the role of the Tis-sue Factor Pathway Inhibitor
in cancer will be discussed.
[Back to top]
Inherited Coagulation Factor VII and X Deficiencies
Associated with Severe Bleeding Diathesis: Molecular Genetics
and Pathophysiology
Keren Borensztajn and C. Arnold Spek
The rare inherited coagulation disorders are a fascinating
group of diseases that have provided us with important insights
into the structure and functions of their respective deficient
proteins. Factor (F)VII deficiency is the commonest of these
inherited disorders of coagulation, whereas FX deficiency
is one of the rarest. Genes encoding the two proteins are
located on the same chromosome at 13q34 and are separated
by 2.8 kb only. Both proteins are vitamin K–dependent
coagulations factors with a very strong structural homology.
This review summarizes current knowledge on the prevalence,
diagnosis and molecular pathology of FVII and FX deficiencies,
and focuses on the genetic abnormalities associated with severe
deficiencies and bleeding diathesis.
[Back to top]
RNA-Based Gene Therapy for Haemophilia B
Maikel P. Peppelenbosch, Francesca Milano, Carmen V. Ferreira,
Anna Knapinska, Sander H. Diks and C. Arnold Spek
Haemophilia B, a deficiency in clotting factor IX (FIX),
occurs in about 1 in 25.000 males. Of these patients, approximately
40% are characterized as having 'severe' haemophilia (FIX
below 1% of normal). Although the use of plasma-derived or
rFIX has extended the lifespan of these patients, they remain
afflicted by a variety of sequelae of the disease. Interestingly,
a relatively small increase in the levels of FIX results in
a dramatic increase in the quality of life, requiring rFIX
substitution only prior to dental and surgical procedures.
This latter trait of the disease suggests that gene therapy
only needs to achieve modest expression and makes this disease
a prime candidate for proof-of-concept of gene therapy. Current
protocols for gene therapy entail the risk of malignant transformation.
In addition the viral vectors may cause substantial pathology.
Hence, the field requires the development of inherently safe
gene therapy. Recently, devel-oped protocols have been developed
to transduce peripheral blood cells with high efficiency using
RNA as a vector. These protocols in which the inherently safe
RNA-based gene therapy approach will be validated and implemented
for haemophilia B will provide in turn providing important
proof-of concept for this type of therapy for more prevalent
dis-eases but requires optimization of this strategy, probably
by enhancing RNA stability using artificial nucleotides and
modified UTRs, enhanced production of protein by codon usage
optimization and the use of multi-cistronic constructs, and
enhanced secretion of the protein employing target cell-tailored
secretion signals.
[Back to top]
Perspectives of Activated Protein C in the Vasculature:
Update on Proposed Roles of the Protein C Pathway
S.H. Slofstra and H. Ten Cate
The protein C anticoagulant pathway serves as a vitally
important system limiting the coagulation response. The pathway
is triggered by thrombin allowing the trombin-thrombomodulin
(TM)-endothelial protein C receptor (EPCR) complex to activate
protein C. The discovery of the protein C pathway and genetic
defects affecting the system in relation to the risk of venous
thrombosis directed most research attention towards its anti-coagulatory
properties. The observation that activated protein C (APC)
has potentially important functions in controlling inflammation
and functioning as a natural defence against sepsis, redirected
research into its cellular functions. Intracellular signaling
effects in endothelial cells induced by APC depend on the
presence of the endothelial protein C receptor and protease
activated receptor-1 and involves a variety of distinct signal
transduction pathways engaged in various biological activities.
However, the exact mechanism by which the protein C pathway
controls inflammation during sepsis and to what extend the
signaling capacity of APC contributes to its pro-survival
effects remains elusive. Other essential factors of the protein
C pathway, like EPCR and TM may themselves be directly involved
in regulating inflammation, underlining the importance of
the complete pathway.
[Back to top]
Atherosclerosis and its Acute Consequences: Insights
from Genetic Association Studies
S. Bezzina Wettinger and P.H. Reitsma
Atherosclerosis and the acute coronary syndromes (ACS) are
very prevalent in the developed world, and they are on the
increase. These complex diseases result from interplay between
genes, lifestyle, and environment. Lifestyle and environmental
factors are now largely known, and research efforts are shifting
towards the discovery of predisposing genetic factors. Several
approaches are being undertaken including family studies,
genetic association studies, and studies in mice. Guided by
our increasingly detailed understanding of the processes underlying
cardiovascular disease many candidate genes have been evaluated
including those encoding adhesion molecules, chemokines and
cytokines, and matrix metalloproteinases.
Genetic association studies using polymorphisms in these
genes have often given conflicting results that are difficult
to judge. The literature on this work will be reviewed here
and some common themes emerge. These include the complexities
surrounding polymorphisms found within a cluster of genes
of related function, the possibility that an underlying condition
that predisposes to endothelial dysfunction is required for
certain polymorphisms to exert their effect, the possibility
that a gene, or another gene tightly linked to it, modifies
risk for a traditional risk factor for atherosclerosis or
its acute effects, and the notion that studying combinations
of genotypes, or combinations of genotypes and predisposing
traditional factors may be a better reflection of the situation
in vivo. The practical difficulties of elucidating such complex
influences are also discussed.
[Back to top]
Vascular Progenitor Cells in the Development of Transplant
Arteriopathy
J.L. Hillebrands, H. Rienstra, G. Onuta and J. Rozing
Although advances in graft procurement, preservation, matching
and immunosuppression have all contributed to today’s
outstanding short-term graft survival rates after solid organ
transplantation, similar success has not been achieved in
preventing chronic transplant dysfunction (CTD) and extending
long-term graft survival. CTD is being recognized as one of
the major causes of long-term (>5 years) graft loss. CTD
is featured by obliteration of the vascular lumen as a result
of occlusive neointima formation referred to as transplant
arteriopathy (TA). Uncontrolled proliferation (hyperplasia)
of smooth muscle cells (SMCs) is in major part responsible
for neointima formation in TA. Endothelial cells (ECs) cover
the neointima and form the barrier between the circulating
blood and the vascular wall. The etiology of TA is largely
unknown and development of TA is refractory to most anti-rejection
therapies. Recent data attribute an important role to host-derived
vascular progenitor cells in the development of TA, and these
cells may be recruited from various sources including the
bone marrow. Vascular progenitor cells are potential targets
for therapeutic intervention to attenuate TA development.
Therefore, understanding the molecular pathways that promote
recruitment of vascular pro-genitor cells, that determine
their differentiation fate, and that determine the proliferative
capacity of their progeny, is warranted to dissect their detrimental
and possible beneficial effects in the development of TA.
[Back to top]
Blood Coagulation and the Risk of Atherothrombosis
Henri M.H. Spronk and Hugo Ten Cate
Atherosclerosis is a multifactorial disease that is caused
by many years of exposure to atherogenic stimuli that already
at a young age lead to early lesions, the so-called “fatty
streaks”. One of the mechanisms involved in atherogenesis
is the activated blood coagulation system, but its primary
role in this process has not been established. From the fatty
streak onwards, evidence of activated coagulation is histologically
present in the form of fibrin/fibrinogen molecules. With advancing
lesions, the presence of tissue factor protein, introduced
by invading macrophages or locally expressed by vascular smooth
muscle cells (VSMC) becomes more prominent. Tissue factor
has been shown to be an important agonist of arterial thrombosis
upon erosion of the luminal plaque surface or frank rupture
of plaques. Recent data indicate the production of factor
VII, probably expressed by VSMC in plaque lesions, which raises
the possibility that formation of a catalytic tissue factor/factor
VIIa complex occurs in the atherosclerotic vessel wall. Theoretically,
such a complex could then induce local generation of thrombin
and fibrin molecules, but its precise role is still unknown.
While fibrinogen/fibrin molecules participate in early plaque
lesions, increased activity of systemic coagulation is of
no major influence on the risk of arterial thrombosis, except
in rare cases where a number of specific procoagulant forces
collide. Despite the presence of tissue factor – factor
VII complex it is unlikely that all fibrin in the atherosclerotic
plaque is the direct result from local clotting activity.
Evidence is accumulating that the tissue factor/factor VII
complex is involved in important coagulation-independent biological
processes (inflammation, cell migration, apoptosis), either
via direct signal transduction through tissue factor
or by (in)direct activation of protease activated receptors.
The presence of localized vascular “mini-cascades”
of coagulation proteins may target a new role of coagulation
in vessel wall remodeling and plaque vulnerability.
[Back to top]
Myocardial Ischemia and Reperfusion Injury: Studies
Using Transgenic and Knockout Mice
W.M.C. Jong, H. Ten Cate, P.H. Reitsma and R.J. de Winter
Transgenic and knockout mice are created and used for a large
variety of research objectives. This overview describes the
(genetically modified) mouse models that have been used to
study the development of myocardial ischemia and reperfusion
injury. The role of cytokines, chemokines, leukocytes, reactive
oxygen species, anti-oxidants, NO, complement system, coagulation
system, heat shock proteins, apoptosis and necrosis, and acute
phase reactants are presented.
[Back to top]
Coagulation and Cancer Therapy: The Potential of Natural
Compounds
Giselle Z. Justo and Carmen V. Ferreira
In the past few years, it has become clear that the processes
of cancer metastasis and invasion are highly dependent on
components of the blood coagulation cascade. Metastasis is
critically dependent on the formation of new blood vessels
and the role of many blood-clotting factors in tumor angiogenesis
has been extensively studied. Angiogenesis constitutes an
important point in the control of cancer progression and in
recent years much attention has been paid to the development
of antiangiogenic agents. Natural compounds constitute a promising
alternative for application in antiangiogenesis therapy due
to their multiple mechanisms of action. Moreover, they can
be used as templates for the production of analogues with
enhanced activity. In this review, the potential of natural
compounds to target blood coagu-lation cascades and to prevent
tumor growth will be highlighted in view of their underlying
mechanisms.
[Back to top]
Molecular Mechanisms Regulating mRNA Stability: Physiological
and Pathological Significance
Anna M. Knapinska, Patricia Irizarry-Barreto, Sri Adusumalli,
Ioannis Androulakis and Gary Brewer
The cytoplasmic level of a messenger RNA, and hence protein,
depends not only upon its rates of synthesis, processing,
and transport, but its decay rate as well. mRNA decay rates
are frequently not static, but vary in response to extracellular
stimuli and viral infections. Sequence elements within an
mRNA, together with the protein and/or small non-coding RNA
factors that bind these elements, dictate its decay rate.
Not surprisingly, genetic alterations in mRNA stability can
lead to various diseases, including cancer, heart disease,
and immune disorders. However, we now have the capacity to
alter selective aspects of the mRNA decay machinery by design
in order to tune expression of any given gene to desired levels
as a means of achieving therapeutic results. Our intent in
this review is to introduce the reader to the intricacies
of regulated gene expression at the level of mRNA stability,
describe the roles of mRNA stability in pathology and drug
development, and discuss some recent developments in the field
of computational biology that are providing novel tools for
understanding specific protein-RNA interactions, which drive
the mRNA degradation machinery.
[Back to top]
Using Microgravity for Defining Novel Anti-Atherosclerotic
Therapy
Auke Verhaar, Kausilia K. Krishnadath and Maikel P. Peppelenbosch
Among the most important insights into coronary and inflammatory
disease is that the formation of vessel occluding placques
is its essence an inflammatory process, that is counteracted
by anti-inflammatory drugs Current therapeutical options of
dealing with the increased challenge to public health posed
by increased vessel disease are limited and unsatisfactory.
Disturbingly, an increasing cohort of patients does not react
to the immunosuppressive drugs available. Importantly, however,
space travel is associated with well-tolerated immunosuppression
and thus identification of the molecular mechanisms underlying
this space travel-associated immunosuppression may have significant
benefit for directing clinical research on earth. Devising
an experimental set up for investigating the molecular details
of space flight-induced immunosuppression is, however, fraught
with difficulties. Two recent ESA-sponsored space missions
(the Delta Taxi flight to ISS and Maser 10 sounding rocket
mission) have now shown that these technical hurdles can be
successfully tackled.
|
