Current Drug Targets - Cardiovascular & Hematological Disorders - Volume 3, Issue 2, 2003

Reviewing advances in cardiology and haematology together may appear at first sight to require some artificiality to make a satisfying fit. For two reasons, at least, this is not the case. Firstly, convergence in biology has become very clear over the past decade and this could not be better illustrated by the demonstration that the haemangioblast is the common progenitor of both haemapoietic stem cells and vascular endothelium. This opens the way to common (and differential) approaches to the manipulation of these cells, a field at present in its infancy. A second convergence is the common goal of understanding the processes resulting in haemostasis, thrombosis and vascular occlusion and the means for developing effective antithrombotics. This is exemplified by a number of agents either in use or in clinical trial as a result of haematological and cardiological collaboration. This collaboration is recognisable with the development, many years ago, of streptokinase and the use of aspirin in vascular disease and continues to this day with specific antiplatelet inhibitors and oral thrombin inhibitors as they become accepted into clinical use over the next few years. Here we review current advances in pharmacological treatments in cardiology and haematology, grouped primarily by disease process, focusing on novel and emerging therapies likely to be of importance in the future.

Platelet adhesion to a damaged blood vessel is the initial trigger for arterial hemostasis and thrombosis. Platelets adhere to the subendothelium through an interaction with von Willebrand factor (VWF), which forms a bridge between collagen within the damaged vessel wall and the platelet receptor glycoprotein Ib / V / IX (GPIb), an interaction especially important under high shear conditions[1]. This reversible adhesion allows platelets to roll over the damaged area, which is then followed by a firm adhesion mediated by the collagen receptors (α2β1, GPVI,...) in addition[2] resulting in platelet activation. This leads to the conformational activation of the platelet αIIb α3 receptor, fibrinogen binding and finally to platelet aggregation.Over the past decades, modulation of platelet function has been a strategy for the control of cardiovascular disease. Lately, drugs have been developed that target the fibrinogen receptor αIIb α3 or the ADP receptor and many of these promising compounds have been tested in clinical trials. However the development of products that interfere with the first step of hemostasis, i.e. the platelet adhesion, has lagged behind. In this review we want to discuss (i) the in vivo studies that were performed with compounds that target proteins involved in different adhesion steps i.e. the VWF-GPIb-axis, the collagen-VWF axis and the collagen-collagen receptor axis and (ii) the possible advantages these putative new drugs could have over the current antiplatelet agents.

One of the principal functions of erythropoietin (EPO) is to stimulate the survival, proliferation, and differentiation of immature erythroid cells. Yet, EPO has recently been shown to modulate cellular signal transduction pathways to perform multiple functions other than erythropoiesis. EPO is cytoprotective through the prevention of programmed cell death in both vascular and neuronal systems by modulating two distinct components of programmed cell death that involve the degradation of genomic DNA and the externalization of cellular membrane phosphatidylserine (PS) residues. Cytoprotection by EPO is initiated by the activation of the EPO receptor (EPOR) and subsequent signal transduction pathways that originate with the Janus-tyrosine kinase 2 (Jak2) protein. Further down-stream cellular pathways include the activation of signal transducers and activators of transcription (STATs), Bcl-xL, phosphoinositide-3-kinase / Akt, mitogen-activated protein kinases, cysteine proteases, protein tyrosine phosphatases, and nuclear factor κB. Further understanding of the cellular pathways that modulate EPO cytoprotection in the nervous system will be crucial for the development of therapeutic strategies against neurodegenerative diseases.

The chorioallantoic membrane (CAM) is widely used as a model to examine angiogenesis, and antiangiogenesis. Its advantages over mammalian systems include low cost, and ease of preparation, as well as the absence of a mature immune system. Although the use of this model presents a major opportunity to compare data generated in different laboratories, thereby expediting the evaluation of new drugs, angiogenic potential of cells and tissues, and body fluids, as well as to provide meaningful information concerning the molecular mechanisms involved, the wide range of methodologies used, especially in the quantification of the response, make any comparison essentially invalid.In this review, the major methodologies for all aspects of the use of the CAM in angiogenesis-related studies have been described. These include the source of the CAM, the methods for culture, and methods for evaluation of normal growth and of the response to an intervention. Methods for applying an intervention, the age for intervention and the duration of an intervention are documented. The structure and growth characteristics, the nature of possible responses to stimulation and inhibition of angiogenesis, and the complications of nonspecific reactions have been examined.The need for a standardized approach to the use of the CAM model is obvious. One set of possible parameters is suggested.

Striated (skeletal and cardiac) muscle is activated by the binding of Ca2+ to troponin C and is regulated by the thin filament proteins, tropomyosin and troponin. Unlike in molluscan or smooth muscles, the myosin regulatory light chains (RLC) of striated muscles do not play a major regulatory role and their function is still not well understood. The N-terminal domain of RLC contains a 'Ca2+-Mg2+'-binding site and, analogous to that of smooth muscle myosin, also contains a phosphorylation site. During muscle contraction, the increase in Ca2+ concentration activates the Ca2+ / calmodulin-dependent myosin light chain kinase and leads to phosphorylation of the RLC. In agreement with other laboratories we have demonstrated that phosphorylation and Ca2+ binding to the RLC play an important modulatory role in striated muscle contraction. Furthermore, the ventricular isoform of human cardiac RLC has been shown to be one of the sarcomeric proteins associated with familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular hypertrophy, myofibrillar disarray and sudden cardiac death. Our recent studies have demonstrated that phosphorylation and Ca2+ binding to human ventricular RLC are significantly altered by the FHC mutations and that their detrimental effects depend upon the specific position of the missense mutation, whether located in the proximity of the RLC 'Ca2+-Mg2+'-binding site or the phosphorylation site (Serine 15). We have also shown that there is a functional coupling between Ca2+ and / or Mg2+ binding to the RLC and phosphorylation and that the FHC mutations can affect this relationship. Further in vivo studies are necessary to investigate the mechanisms involved in the pathogenesis of RLC-linked FHC.