|
Cardiovascular
& Hematological Disorders - Drug Targets
ISSN: 1871-529X
Current Drug Targets - Cardiovascular
& Hematological Disorders
Volume 8, Number 1, March 2008
Contents
Immunomodulation Via Targeted Inhibition of Antige
Receptor Signal Transduction Pp. 1-6
Andrew E. Schade and Gonzalo Gonzalez-Stawinski
[Abstract]
Adiponectin and its Role in Cardiovascular Diseases
Pp. 7-46
Jerzy Beltowski, Anna Jamroz-Wisniewska and Sylwia Widomska
[Abstract]
Reduction of Myocardial Ischemia-Reperfusion
Injury with Pre- and Postconditioning: Molecular Mechanisms
and Therapeutic Targets Pp. 47-65
Michael M. Galagudza, Ilia O. Blokhin, Aleksey A. Shmonin
and Kirill A. Mischenko
[Abstract]
Receptor Subtype Abundance as a Tool for Effective
Intracellular Signalling Pp. 66-79
Jaromír Myslivecek, Martina Nováková
and Martin Klein
[Abstract]
Mast Cells and Inflammatory Heart Disease: Potential
Drug Targets Pp. 80-90
DeLisa Fairweather and Sylvia Frisancho-Kiss
[Abstract]
Abstracts
[Back to top]
Immunomodulation Via Targeted Inhibition of Antigen
Receptor Signal Transduction
Andrew E. Schade and Gonzalo Gonzalez-Stawinski
Coronary artery vasculopathy (CAV), characterized by
diffuse concentric coronary artery intimal thickening with
fibrosis, remains a significant complication impeding long
term engraftment in heart transplantation. The pathophysiologic
processes driving CAV are not well understood, however T cell
mediated cellular immunity and cytokines have been implicated.
The inability to prevent CAV may be related in part to a limited
spectrum of inhibition that that current immunosuppressive
therapies exhibit against second messenger pathways elicited
by T cell receptor (TCR) activation and dose limiting toxicities.
Therefore, considering that antigen specific T cell activation
is initiated at the TCR, including alloresponses involving
direct and indirect antigen presentation, targeting the proximal
kinases involved in this process may provide novel therapeutic
options for controlling rejection. Src family kinases (SFK),
particularly p56lok (Lck)
and p59fyn (Fyn), are intimately
associated with the earliest signaling events through the
TCR and could provide targets for immunomodulatory agents.
Such targeted inhibition of TCR signaling may institute a
novel approach for diminishing the T cell mediated response
associated with CAV. In this review we discuss therapeutic
agents that have been shown to inhibit SFK and the rationale
for investigating the potential application of these agents
in heart transplantation.
[Back to top]
Adiponectin and its Role in Cardiovascular Diseases
Jerzy Beltowski, Anna Jamroz-Wisniewska and Sylwia Widomska
Studies performed during the last decade indicate that
adipose tissue is not only a site of triglyceride storage
but also an active endocrine organ which secretes many biologically
active mediators referred to as “adipokines”.
In contrast to many adipokines which are overproduced in obese
individuals and exert deleterious effects on insulin sensitivity,
lipoprotein metabolism and cardiovascular system, such as
leptin, tumor necrosis factor-α,
plasminogen activator inhibitor-1, resistin, etc., adiponectin
seems to be a unique adipokine which is produced in lower
amounts in obese than in lean subjects and possesses predominantly
beneficial activities, i.e. increases insulin sensitivity,
stimulates fatty acid oxidation, inhibits inflammatory reaction
and induces endothelium-dependent nitric oxide-mediated vasorelaxation.
Adiponectin binds two receptors, AdipoR1 and AdipoR2. Adiponectin
knockout mice exhibit various manifestations of the metabolic
syndrome such as insulin resistance, glucose intolerance,
hyperlipidemia, impaired endothelium-dependent vasorelaxation
and hypertension, as well as augmented neointima formation
after vascular injury. Clinical studies indicate that plasma
adiponectin concentration is lower in patients with essential
hypertension and ischemic heart disease. Raising endogenous
adiponectin level or increasing the sensitivity to this hormone
may be a promising therapeutic strategy for patients with
metabolic and cardiovascular diseases. Among currently used
drugs, thiazolidinediones (peroxisome proliferator activated
receptor γ
agonists) are most effective in elevating adiponectin level.
[Back to top]
Reduction of Myocardial Ischemia-Reperfusion Injury with Pre-
and Postconditioning: Molecular Mechanisms and Therapeutic
Targets
Michael M. Galagudza, Ilia O. Blokhin, Aleksey A. Shmonin
and Kirill A. Mischenko
Reduction of infarct size as well as alleviation of other
ischemia- and reperfusion-associated injuries are the goals
of primary importance in cardiology. One of the remedies is
considered to be myocardial preconditioning (PreCon) referred
usually to as an increased myocardial tolerance to prolonged
ischemia following brief ischemic or non-ischemic challenge.
In this review, PreCon stimuli tested to date are considered
including a number of mildly noxious factors applied either
locally to the myocardium or systemically. Recently, one more
mode of heart protection against reperfusion injury termed
postconditioning (PostCon) has been developed. On the basis
of ample evidence published, along with our findings, a detailed
comparative analysis of PreCon and PostCon is presented, with
special emphasis on the cellular, molecular, and pharmacological
aspects of the topic as well as clinical applications, both
implemented and awaiting practical approval.
[Back to top]
Receptor Subtype Abundance as a Tool for Effective Intracellular
Signalling
Jaromír Myslivecek, Martina Nováková
and Martin Klein
The regulation of heart function is one of the essentials
for the survival of organism. Therefore, the effective mechanisms
of regulation can minimize the energy requirements and improve
the ability to react to different needs on time and appropriately
.
Two receptor types, β-adrenoceptors
and muscarinic receptors, with almost antagonistic function,
are “basic regulators” of the heart parameters.
It is relevant to mention that beside the main adrenoceptors
and muscarinic receptors subtypes (β2-
and M2-subtype), other minor
subtypes that regulate heart function, i.e. β2
-, β3
-adrenoceptors, α1
-adrenoceptors and minor subtypes of muscarinic
receptors (M1, M3
and M5) are present in the
heart. In this regard is intriguing that just two ca-techolamines
(adrenaline, noradrenaline) have many “targets”
– receptors that differ so much in the functional consequences
of their activation: while β1-
and β2-adrenoceptors
cause cardiostimulation, β3-adrenoceptors
are responsible for cardioinhibition and α1-adrenoceptors
contribute to enhanced inotropy. Similarly, some data show
that other muscarinic receptors than M2
muscarinic subtype, are expressed in the heart and these minor
subtype(s) can contribute to the heart regulation in similar
way as β3
-adrenoceptors to the catecholamine action.
Taken together, regulation of heart function through different
receptor subtypes and using homologous and heterologous regulation
can represent an effective tool for coping with permanently
changing environmental conditions.
[Back to top]
Mast Cells and Inflammatory Heart Disease: Potential Drug
Targets
DeLisa Fairweather and Sylvia Frisancho-Kiss
Inflammation underlies the pathogenesis of many common
cardiovascular diseases (CVD) such as myocardial infarction,
atherosclerosis, myocarditis and dilated cardiomyopathy. Allergic
disorders like allergic rhinitis and asthma, both chronic
inflammatory conditions, have recently been linked to increased
CVD and death. Studies have found that increased IgE levels,
eosinophilia, positive skin-prick tests, self-reported asthma
and enzymes that regulate leukotriene synthesis (5-lipoxygenase)
predict a high risk for atherosclerosis, stroke and myocardial
infarction. Mast cells (MCs), cells involved in the pathogenesis
of allergy and asthma, are emerging as key players in the
regulation of inflammation and fibrosis in the heart and vasculature.
Our laboratory has found that MC numbers are increased in
mice susceptible to developing chronic dilated cardiomyopathy.
The fibrosis associated with chronic heart disease is increased
by MC degranulation. MCs can also act as antigen-presenting
cells increasing inflammation in the heart through Toll-like
receptor-4 signaling and increased proinflammatory cytokine
production. Similar inflammatory mechanisms are observed for
myocarditis and atherosclerosis. Many of the drugs currently
used to reduce heart disease act on mediators/ pathways downstream
of MC degranulation. An improved understanding of the role
of MCs in regulating inflammation and fibrosis will enable
researchers and clinicians to better treat heart disease.
|
