Cardiovascular
& Hematological Agents in Medicinal Chemistry
ISSN: 1871-5257
Cardiovascular & Hematological
Agents in Medicinal Chemistry
Volume 7, Number 1, January 2009
Contents
The Intermediate-Conductance Ca2+-Activated
K+ Channel (KCa3.1)
in Vascular Disease Pp. 1-11
D.L. Tharp and D.K. Bowles
[Abstract] [Full
text article] [PMID:
19149539 PubMed - indexed for MEDLINE]
Current Status of Pharmacological Thrombolytic
Therapy and Mechanical Thrombectomy for the Treatment of Acute
Deep Venous Thrombosis Pp. 12-18
T.J. Kiernan, B. Cepeda, G.D. Kiernan and B.P.
Yan
[Abstract] [Full
text article] [PMID:
19149540 PubMed - indexed for MEDLINE]
Nucleotide-Derived Thrombin Inhibitors: A New
Tool for an Old Issue Pp. 19-28
S. Lancellotti and R. De Cristofaro
[Abstract] [Full
text article]
[PMID:
19149541 PubMed - indexed for MEDLINE]
Role of Natriuretic Peptide Family in Cardiovascular
Medicine Pp. 29-42
B.B. Das and R. Solinger
[Abstract] [Full
text article]
[PMID:
19149542 PubMed - indexed for MEDLINE]
Natriuretic Peptides in Cardiovascular Diseases
of Fetus, Infants and Children Pp. 43-51
B.B. Das, S. Raj and R. Solinger
[Abstract]
[Full
text article] [PMID:
19149543 PubMed - indexed for MEDLINE]
mTOR in Growth and Protection of Hypertrophying
Myocardium Pp. 52-63
S. Balasubramanian, R.K. Johnston, P.C. Moschella, S.K.
Mani, W.J. Tuxworth, Jr. and D. Kuppuswamy
[Abstract] [Full
text article] [PMID:
19149544 PubMed - indexed for MEDLINE]
Antiarrhythmic Drug Therapy for Atrial Fibrillation:
Focus on Atrial Selectivity and Safety Pp. 64-75
D. Li, H. Sun and P. Levesque
[Abstract]
[Full
text article] [PMID:
19149545 PubMed - indexed for MEDLINE]
Inflammatory Cardiovascular Risk Markers in Obstructive
Sleep Apnoea Syndrome Pp. 76-81
S. Ryan and W.T. McNicholas
[Abstract] [Full
text article]
[PMID:
19149546 PubMed - indexed for MEDLINE]
Insights Into the Role of microRNAs in Cardiac
Diseases: From Biological Signalling to Therapeutic Targets
Pp. 82-90
E. Zorio, P. Medina, J. Rueda, J.M. Millán, M.A.
Arnau, M. Beneyto, F. Marín, J.R. Gimeno, J. Osca,
A. Salvador, F. España and A. Estellés
[Abstract] [Full
text article]
[PMID:
19149547 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[PMID:
19149539 PubMed - indexed for MEDLINE]
The Intermediate-Conductance Ca2+-Activated
K+ Channel (KCa3.1)
in Vascular Disease
D.L. Tharp and D.K. Bowles
[Full
text article]
The intermediate-conductance Ca2+-activated
K+ channel (KCa3.1)
was first described by Gardos in erythrocytes and later confirmed
to play a significant role in T-cell activation and the immune
response. More recently, KCa3.1
has been characterized in numerous cell types which contribute
to the development of vascular disease, such as T-cells, B-cells,
endothelial cells, fibroblasts, macrophages, and dedifferentiated
smooth muscle cells (SMCs). Physiologically, KCa3.1
has been demonstrated to play a role in acetycholine and endothelium-derived
hyperpolarizing factor (EDHF) induced hyperpolarization, and
thus control of blood pressure. Pathophysiologically, KCa3.1
contributes to proliferation of T-cells, B-cells, fibroblasts,
and vascular SMCs, as well as the migration of SMCs and macrophages
and platelet coagulation. Recent studies have indicated that
blockade of KCa3.1, by specific
blockers such as TRAM-34, could prove to be an effective treatment
for vascular disease by inhibiting T-cell activation as well
as preventing proliferation and migration of macrophages,
endothelial cells, and SMCs. This vasculoprotective potential
of KCa3.1 inhibition has
been confirmed in both rodent and swine models of restenosis.
In this review, we will discuss the physiological and pathophysiological
role of KCa3.1 in cells closely
associated with vascular biology, and the effect of KCa3.1
blockers on the initiation and progression of vascular disease.
[Back to top]
[PMID:
19149540 PubMed - indexed for MEDLINE]
Current Status of Pharmacological Thrombolytic Therapy and
Mechanical Thrombectomy for the Treatment of Acute Deep Venous
Thrombosis
T.J. Kiernan, B. Cepeda, G.D. Kiernan and B.P.
Yan
[Full
text article]
Deep venous thrombosis (DVT) is a highly prevalent clinical
problem associated with significant mortality and morbidity.
In the United States alone, it is estimated that DVT affects
approximately 50 per 100,000 people per year. This results
in >600,000 inpatient and outpatient treatments per year
and accounts for approximately 100,000 deaths from thromboembolic
complications. Post-thrombotic syndrome (PTS) is associated
with serious long-term physical, social and economic sequelae
for patients. In this article, we attempt to perform a contemporary
review of the literature pertaining to the use of thrombolytic
therapy and endovascular thrombectomy in the treatment of
acute DVT.
[Back to top]
[PMID:
19149541 PubMed - indexed for MEDLINE]
Nucleotide-Derived Thrombin Inhibitors: A New Tool for an
Old Issue
S. Lancellotti and R. De Cristofaro
[Full
text article]
Aptamer molecules represent an attractive approach in
pharmacological therapy. Thrombin is a plasma serine protease
that plays a key role in coagulation and haemostasis, also
playing a relevant role in endothelial and smooth muscle cell
functions. Thus, the development and use of direct thrombin
inhibitors represents a potent tool in cardiovascular therapeutics.
This review describes the status of direct thrombin inhibitors,
focusing on aptamer-based drug candidates, that are at present
in pre-clinical and in clinical trials. In addition, more
recent research strategies in the design of novel aptamer
thrombin inhibitors are presented and discussed. In particular,
their structural, conformational, pharmacokinetic and pharmacodynamic
properties are discussed in relation with the specificity
of their binding to relevant thrombin exosites, which regulate
the enzyme interaction with natural substrates and cellular
receptors. Despite the addition of new effective anticoagulants
to the therapeutic armoury, there remains a need for safer
and effective anticoagulants. The aptamer-based thrombin inhibitors
may represent an attractive approach for future developments
of more potent and safer anticoagulants.
[Back to top]
[PMID:
19149542 PubMed - indexed for MEDLINE]
Role of Natriuretic Peptide Family in Cardiovascular Medicine
B.B. Das and R. Solinger
[Full
text article]
The natriuretic peptides (NP) are a group of structurally
similar but genetically distinct peptides with many favorable
physiological properties that have emerged as important candidates
for development of diagnostic tools and therapeutic agents
in cardiovascular diseases. The NP family includes atrial
natriuretic peptide (ANP, 28AA), urodilatin (INN: Ularitide,
32 AA), B-type natriuretic peptide (BNP, 32AA), C-type natriuretic
peptide (CNP, 22AA), and D-type natriuretic peptide (DNP,
38AA). They share common features and exhibit tissue distribution
of gene expression as well as functional and pharmacological
characteristics. The primary sites of synthesis of the NP
are the heart and brain; additional extra cardiac and extra
cranial sites include intestine and kidney. Membrane-bound
guanyl cyclase-coupled NP receptors (NPR) (A- and B- types)
are generally implicated in mediating NP effects via
the production of cyclic GMP as the intra-cellular messenger.
NPR-C lacking the guanyl cyclase domain may influence the
target cell function through inhibitory guanine nucleotide
(Gi) protein, and they likely also act as clearance receptors
for circulating peptides. NPs are identified as regulatory
diuretic-natriuretic substances responsible for salt and water
homeostasis and as hormones lowering blood pressure. This
review discusses the essential biochemistry, physiological
properties of NP and their manifold functional implications
in cardiovascular medicine.
[Back to top]
[PMID:
19149543 PubMed - indexed for MEDLINE]
Natriuretic Peptides in Cardiovascular Diseases of Fetus,
Infants and Children
B.B. Das, S. Raj and R. Solinger
[Full
text article]
The natriuretic peptides (NP) appear to be functional
by midgestation, respond to volume stimuli, and regulate blood
pressure and salt and water balance in the developing embryo.
In addition, the NP may help regulate the blood supply to
the fetus, acting as vasodilators in the placental vasculature.
Peaks of ANP and BNP expression during gestation coincide
with significant events in cardiac organogenesis, suggesting
a role for NP in the formation of the heart. Levels of atrial
natriuretic peptide (ANP) are higher in the fetal circulation
than in adults, and fetal ventricles express higher levels
of ANP and B-type natriuretic peptide (BNP) than adult ventricles.
In this comprehensive review we have discussed the role NP
during development of the fetal heart and circulation and
in various cardiovascular diseases of neonatal and pediatric
age group.
[Back to top]
[PMID:
19149544 PubMed - indexed for MEDLINE]
mTOR in Growth and Protection of Hypertrophying Myocardium
S. Balasubramanian, R.K. Johnston, P.C. Moschella, S.K.
Mani, W.J. Tuxworth, Jr. and D. Kuppuswamy
[Full
text article]
In response to an increased hemodynamic load, such as
pressure or volume overload, cardiac hypertrophy ensues as
an adaptive mechanism. Although hypertrophy initially maintains
ventricular function, a yet undefined derailment in this process
eventually leads to compromised function (decompensation)
and eventually culminates in congestive heart failure (CHF).
Therefore, determining the molecular signatures induced during
compensatory growth is important to delineate specific mechanisms
responsible for the transition into CHF. Compensatory growth
involves multiple processes. At the cardiomyocyte level, one
major event is increased protein turnover where enhanced protein
synthesis is accompanied by increased removal of deleterious
proteins. Many pathways that mediate protein turnover depend
on a key molecule, mammalian target of rapamycin (mTOR). In
pressure-overloaded myocardium, adrenergic receptors, growth
factor receptors, and integrins are known to activate mTOR
in a PI3K-dependent and/or independent manner with the involvement
of specific PKC isoforms. mTOR, described as a sensor of a
cell's nutrition and energy status, is uniquely positioned
to activate pathways that regulate translation, cell size,
and the ubiquitin-proteasome system (UPS) through rapamycin-sensitive
and -insensitive signaling modules. The rapamycin-sensitive
complex, known as mTOR complex 1 (mTORC1), consists of mTOR,
rapamycin-sensitive adaptor protein of mTOR (Raptor) and mLST8
and promotes protein translation and cell size via
molecules such as S6K1. The rapamycin-insensitive complex
(mTORC2) consists of mTOR, mLST8, rapamycin-insensitive companion
of mTOR (Rictor), mSin1 and Protor. mTORC2 regulates the actin
cytoskeleton in addition to activating Akt (Protein kinase
B) for the subsequent removal of proapoptotic factors via
the UPS for cell survival. In this review, we discuss pathways
and key targets of mTOR complexes that mediate growth and
survival of hypertrophying cardiomyocytes and the therapeutic
potential of mTOR inhibitor, rapamycin.
[Back to top]
[PMID:
19149545 PubMed - indexed for MEDLINE]
Antiarrhythmic Drug Therapy for Atrial Fibrillation: Focus
on Atrial Selectivity and Safety
D. Li, H. Sun and P. Levesque
[Full
text article]
Atrial fibrillation (AF) is a highly prevalent arrhythmia
and responsible for significant morbidity, mortality and health
care cost. The prevalence of AF is expected to increase markedly
with the aging population. The use of conventional antiarrhythmic
agents has been limited by potentially fatal ventricular proarrhythmia.
Rhythm control could become the preferred treatment strategy
for AF if antiarrhythmic agents that are similarly or more
effective, but safer, than currently approved AF agents become
available. A subanalysis of the Atrial Fibrillation Follow-Up
Investigation of Rhythm Management (AFFIRM) trial data showed
that normal sinus rhythm confers a survival benefit in AF,
suggesting that rhythm control, if achieved without the adverse
effects related to current antiarrhythmic medications, may
offer a significant survival advantage over rate control.
Considerable work has been performed to explore novel, potentially
safer antiarrhythmic drug targets for AF therapy, and some
of these drug targets are currently being tested in experimental
and clinical proof of concept studies. This article summarizes
relevant aspects of the cellular electrophysiology of AF and
re-views the actions of pharmacological agents being considered
for the prevention and treatment of AF, focusing on atrial
selective antiarrhythmic agents. A variety of drugs that inhibit
the atrium-specific ultra rapid delayed rectifier potassium
current (IKur) are being evaluated pre-clinically, but human
experience with these agents is limited. The acetylcholine-activated
current (IKACh) is another novel candidate target for atrial-specific
drug therapy. The constitutively active form of this current
is increased in human AF and pharmacological inhibition might
be of therapeutic value. Certain drugs have IKACh blocking
properties, but similar to IKur-blockers, none have been shown
to have pure selectivity for this current. Newer agents being
studied also include gap junction modulators and angiotensin-converting
enzyme inhibitors. There is great hope that at least some
of these agents will ultimately be available for effective
and safer clinical treatment and prevention of AF.
[Back to top]
[PMID:
19149546 PubMed - indexed for MEDLINE]
Inflammatory Cardiovascular Risk Markers in Obstructive Sleep
Apnoea Syndrome
S. Ryan and W.T. McNicholas
[Full
text article]
Obstructive sleep apnoea syndrome (OSAS) represents a
highly prevalent disease and is recognized as a major public
health burden. Large-scale epidemiological studies have demonstrated
an independent relationship between OSAS and various cardiovascular
disorders. The pathogenesis of cardiovascular complications
in OSAS is not completely understood, but given the complexity
of the disorder, a multifactorial etiology is likely.
Inflammatory processes have emerged as critical in the pathogenesis
of atherosclerosis in general and they mediate many of the
stages of atheroma formation. Circulating levels of several
markers of inflammation have been associated with future cardiovascular
risk. These markers include cell adhesion molecules such as
intercellular adhesion molecule-1 (ICAM-1) and selectins,
cytokines such as tumour necrosis factor alpha (TNF-α)
and interleukin 6 (IL-6), chemokines such as IL-8, and C-reactive
protein (CRP).
There is increasing evidence that inflammatory processes also
play a central role in the cardiovascular pathophysiology
of OSAS. This is supported by cell culture and animal studies
identifying a preferential activation of inflammatory pathways
by intermittent hypoxia (IH), the hallmark of OSAS. A number
of studies have selectively examined the expression of in-flammatory
factors in OSAS patients with different conclusions. These
different findings may have been contributed to by a number
of methodological factors such as small subject numbers, inadequately
matched study populations, particularly in terms of body mass
index (BMI), and inclusion of patients with pre-existing cardiovascular
or metabolic diseases.
This review will focus on the potential role of various inflammatory
markers in OSAS with a critical analysis of the current literature.
[Back to top]
[PMID:
19149547 PubMed - indexed for MEDLINE]
Insights Into the Role of microRNAs in Cardiac Diseases:
From Biological Signalling to Therapeutic Targets
E. Zorio, P. Medina, J. Rueda, J.M. Millán, M.A.
Arnau, M. Beneyto, F. Marín, J.R. Gimeno, J. Osca,
A. Salvador, F. España and A. Estellés
[Full
text article]
microRNAs have recently opened new pathways to explain
gene expression and disease biology in many scenarios, including
cardiac diseases. microRNAs are endogenous small non-coding
RNAs that mediate post-transcriptional repression or messenger
RNA degradation. By annealing to inexactly complementary sequences
in the 3’ untranslated region of the target messenger
RNA, protein level is down-regulated. Several microRNAs appear
to act cooperatively through multiple target sites in one
gene and, conversely, most microRNAs can target several genes.
miR-133 and miR-1 are specifically expressed in cardiac and
skeletal muscle and control myogenesis, cardiac development,
cardiac performance and cardiomyocyte hypertrophy (mainly
by tuning transcription factors and other growth-related targets).
They also modulate the expression of certain cardiac ion channels
and related proteins with proarrhythmic effect. Besides them,
other microRNAs have been shown to exert influence on the
myocardial growth, the electrical balance and the angiogenesis
processes that take place in the heart. Bioinformatics is
a useful tool to identify potential targets of a given microRNA,
although there is still substantial concern about their reliability.
Experimental manipulation of microRNAs has provided a tantalizing
basis to speculate that future research on microRNAs may yield
important progress in the prevention of sudden cardiac death
and in the treatment of cardiac heart failure. However, the
final effect of the blockage of microRNAs in vivo
remains unclear, since each of them can target hundreds of
genes with different intensity. The era of the microRNAs in
cardiovascular diseases has just started.
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