Current Medicinal Chemistry - Cardiovascular & Hematological Agents - Volume 3, Issue 4, 2005

Platelet glycoprotein (GP)Ib-IX-V and GPVI are unique platelet receptors that bind von Willebrand factor or collagen, respectively, and control the initial interaction of circulating platelets with the blood vessel wall in physiology (hemostasis) or pathology (heart attack or stroke). Engagement of GPIbα (the major ligand-binding subunit of GPIb-IXV) by von Willebrand factor or GPVI by collagen, leads to mobilization of cytosolic Ca2+, secretion of platelet agonists such as ADP, cytoskeletal changes, and activation of the platelet integrin λIIβ3 that mediates von Willebrand factor- or fibrinogen-dependent platelet aggregation. Recent evidence suggests the cytosolic regulatory protein, calmodulin, plays a central role in regulating GPVI or GPIβ-IX-V: first, calmodulin directly binds to conserved, juxtamembrane motifs within cytoplasmic domains of both GPVI and GPIb-IX-V (GPIb and GPV subunits) on resting platelets, interactions that dissociate upon platelet activation; second, an intact calmodulin-binding site within GPVI in transfected cells is required for Ca2+ signaling, but not for GPVI-dependent pathways involving Src family kinases or co-associated FcRγ-chain; and third, calmodulin regulates metalloproteinase-dependent ectodomain shedding of GPVI and GPV from human platelets. Other vascular cell adhesion receptors, i.e. leukocyte L-selectin, or PECAM-1 (platelet-endothelial cell adhesion molecule-1), also bind calmodulin within the juxtamembrane region of their cytoplasmic tails, an interaction involved in their proteolytic regulation. Further studies should define the precise functional role of calmodulin in thrombus formation initiated by GPIb-IX-V or GPVI.

Homocysteine (Hcy) is a sulphur-containing amino acid product of methionine's metabolism. Hyperhomocysteinemia (HHcy) is considered an independent risk factor for cardiovascular (CV) disease, at least in highrisk patients. In fact, evidence indicates that although mild HHcy may be regarded as a minor risk factor for CHD in lowrisk patients, it can play a role in triggering new events in patients with known CHD, also by interacting with the "classical" CV risk factors. This is of much interest because HHcy represents a correctable risk factor, inasmuch vitamin supplementation as has been shown to effectively lower total homocysteine plasma levels (tHcy). While case-control and cross-sectional studies have consistently demonstrated an association of HHcy with CV disease, prospective studies have given conflicting results. Moreover, the effect of the homocysteine-lowering treatment in preventing CV events is still under debate. Thus, it remains unclear which patients should be screened for HHcy and which ones should be treated to lower tHcy. In this paper we shall report and discuss knowledge on the potential role of HHcy in the development of CHD and on the benefits due to tHcy-lowering treatment with vitamins.

Anemia is a common finding in chronic heart failure (CHF). Anemia develops due to CHF, but is also known to cause heart failure. Patients with CHF are limited by exercise capacity and fatigue. Low hemoglobin concentration can account for both and may substantially contribute to the symptoms of CHF. Increasing severity of CHF is associated with a higher frequency of anemia, which also becomes clinically more relevant. Anemia has been shown to predict impaired survival in CHF, independent of established prognostic markers. There are many potential reasons for development of anemia in CHF, such as bone marrow depression, reduced intestinal iron uptake and hemodilution as a consequence of sodium and water retention. In most cases, however, anemia in CHF should be viewed as "anemia of chronic illness", being the result of a combination of many factors related to the disease, particularly chronic inflammation. The option of therapeutically targeting anemia in CHF is an intriguing novel approach to improve morbidity and potentially mortality in these patients.

Accumulating evidence strongly implicates the critical roles of intracellular signaling of angiotensin II (AngII) in mediating cardiovascular diseases such as hypertension, atherosclerosis, and restenosis after vascular injury. The importance of AngII signals has also been reported in endothelial dysfunction and insulin resistance, two strong predictors of cardiovascular disease. Through its G protein-coupled AngII type-1 receptor (AT1), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases and serine/threonine kinases. Activation of these kinases requires both G protein-dependent and independent pathways, reactive oxygen species and a metalloprotease, and each kinase could be involved specifically in mediating pathophysiological function of the AT1 receptor target organs. In fact, some of the kinases are indispensable for AngII-induced hypertrophy and migration. The role of these AT1-activated kinases in mediating vascular remodeling, vascular contractility, endothelial dysfunction, and insulin resistance will be discussed in this review. In addition, the AT1 receptor undergoes rapid phosphorylation, desensitization, and internalization upon AngII stimulation. Recent studies with site-directed mutagenesis of the AT1 receptor not only elucidated a G protein interaction and desensitization of the receptor, but also demonstrated a structural requirement of the receptor for downstream signal transduction. Thus, AT1 mutants have provided an excellent means to examine the mechanism of signal transduction and their significance in mediating AngII function. Taken together, in this review, we will focus our discussion on the recent findings of the signal transduction research elucidating novel signaling mechanisms of the AT1 receptor that are relevant to the vascular pathophysiology of AngII.

Systemic inflammatory response syndrome (SIRS) with activation of molecular cascades, cell activation, accumulation of interstitial fluid, organ dysfunction and, occasionally, organ failure is still a commonly recognized consequence of cardiac surgery. SIRS leads to costly complications and several strategies intended to ameliorate the symptoms that have been studied, including leukocyte reduction, using filtration. Although, the body of work suggests that leukoreduction attenuates SIRS, discrepancies remain within the literature. The recent literature is reviewed highlighting the areas where concordance is lacking. In our study, on the basis of indirect indicators of SIRS, platelet function by thromboelastography biomaterial evaluation by light and scanning electron microscopy, we present our conclusions regarding clinical outcomes and the role of leukofiltration.

This review highlights the most important research data related to membrane potential and current changes in cardiomyocytes during hypotonic stress. Relative decrease in osmolarity in extracellular compartment (due to accumulation of metabolic products in the cells) during acute episodes of ischemia in the heart muscle leads to cell swelling caused by water entering the cells. Such condition starts regulatory volume decrease (RDV) in cardiomyocytes - a process involving activation of various ion channels. It seems to be the crucial proarrhythmic mechanism in ischemic heart, probably very often responsible for sudden cardiac death. Understanding of electrophysiological changes during hypotonic stress of cardiomyocytes is a basis for appropriate pharmacological intervention preventing serious arrhythmias. For instance, outwardly rectifying swelling-induced chloride currents (IClswell), inwardly rectifying non-selective cation current (INSC) and slow component of delayed rectifier K+ currents (IKs) are activated during hypotonic stress in ventricular myocytes and substances like anthracene-9-carboxylic acid (9-AC), chromanol (293B) and gadolinium (Gd3+), able to modulate former channels, should be considered to be potential antiarrhythmic drugs in the near future.

Thrombolysis is conventionally regarded as dissolution of the fibrin matrix of thrombi by plasmin, a protease generated by plasminogen activators from its inactive precursor, plasminogen. Typically plasminogen activation occurs on the surface of the clot, where fibrin behaves as a cofactor in this process, and plasmin also initiates its proteolytic action at the fluid-solid interface. Although the basic reactions of the plasminogen/plasmin system in fluid phase are well characterized in terms of classical enzymology, they cannot explain completely the interfacial fibrinolytic events. Recently new methods have been introduced for quantitative evaluation of plasminogen activation on gel-phase fibrin and heterogenous-phase proteolysis, an overview of the new methodology is presented. Following formation of an interfacial lytic zone, fibrin dissolution proceeds through propagation of this zone to the core of the clot, which depends on diffusion and permeation phenomena affected by the composition of thrombi. Phospholipids (originating from platelets) form a diffusion barrier to the thrombolytic agents and also bind some of them; structural cellular proteins (namely myosin) interact with the fibrin fibers masking their cofactor and plasmin-cleavage sites. The contribution of these recent findings to our understanding of the limitations of current thrombolytic therapy is discussed. Finally, attention is focused on the termination of thrombus-associated proteolytic action in an environment abundant in proteinase inhibitors. Thus, combining together the interfacial events in the initiation, progress and termination of thrombolysis, a concept for modeling the thrombus as a temporary fibrinolytic compartment is presented.

Thrombosis is the most important underlying mechanism of coronary heart disease and embolic stroke. Therefore, antithrombotic therapy is commonly used in cardiovascular diseases. Unfortunately, the benefits are limited, and an important proportion of treated patients will suffer a new thrombotic event. Lack of clinical benefits may be related to heterogeneous response to antithrombotic treatment among individuals (inter-individual heterogeneity). Few factors have been identified to be involved in this inter-individual heterogeneity. Recently, pharmacogenetic has emerged as a new field in medicine that tries to identify gene variants able to explain the heterogeneity in patient's response to a drug. Polymorphisms affecting disposition, metabolism, transporters or targets of the drug could modify the individual response to one therapy, and probably its side effects. The present review article explores the genetic influence on antithrombotic drug efficacy, analysing the modulating role of different polymorphisms on individuals' response to drugs commonly used in current day practice.

HIV infection is associated with a myriad of hematopoietic abnormalities. Thrombocytopenia (TCP), the condition in which platelet counts fall below 150 x 103/mm3 in two or more consecutive platelet counts, is a condition frequently seen in HIV infected individuals regardless of HIV status, gender, or age. Having recently been associated with rapid disease progression, and by complicating the management of AIDS patients, thrombocytopenia has become a medical challenge, highlighting the urgent need for evidence-based treatment protocols in this area. Due to the physiopathology of HIV, therapeutic options currently available for TCP in this already vulnerable population are severely limited. Whereas clinicians often intervene to prevent life-threatening, thrombocytopeniaassociated outcomes in the general population, there is no intervention protocol: for the HIV subjects. Management of the condition seems to be the norm for these individuals. As a result, thrombocytopenia in HIV is a subject that is in urgent need of re-examination. In this review, the importance of thrombocytopenia and current knowledge regarding the physiopathology of HIVassociated thrombocytopenia is discussed, and an overview of current and under-investigation treatment approaches to this adverse hematological condition is provided.

The severity of metabolic syndrome depends on the degree of insulin resistance. However, currently there is no adequate clinical marker for quantitative analysis of insulin resistance. A small quantity of lipoprotein lipase (LPL) protein, which is an inactive form and commonly called 'preheparin LPL mass', exists in serum and i s detected by a sensitive immunoassay system. Recent studies have reported the clinical significance of serum preheparin LPL mass levels in various aspects. For example, preheparin LPL mass is negatively related to serum triglyceride and positively related to HDL-cholesterol, is low in type 2 diabetes mellitus, is increased by administration of insulin sensitizer, and shows an inverse relationship with visceral adiposity. Furthermore, preheparin LPL mass level is significantly lower in patients with coronary atherosclerosis compared to patients with no lesion, and correlates negatively with the severity of these lesions. From these reports, preheparin LPL mass may be considered to be the most important quantitative indicator of insulin resistance of the whole body.

In the past few years, there has been a growing interest in the heptapeptide Angiotensin(Ang)-(1-7), mainly because of its ability to counter regulate many of Ang II actions. Furthermore, heart and blood vessels are important target tissues for Ang-(1-7) formation and actions. The introduction of novel tools, such as the Ang-(1-7) antagonists, A-779 and D-pro7-Ang-(1-7), the Ang-(1-7) agonist AVE 0991, transgenic rats TGR(A-1-7)3292, and use of liposome-encapsulated Ang-(1-7) for evaluating the biochemical and functional role of Ang-(1-7), have produced a great impact in this field of research. Moreover, the recent identification of the Ang-(1-7)-forming enzyme ACE2 and of the Ang-(1-7) receptor Mas will allow important advances in our understanding of the physiological and pathological role of this peptide. In this review, we will discuss the current knowledge concerning the biological effects of Ang-(1-7) in the blood, heart, and blood vessels. In addition, we will highlight the possible applications of agonists of its receptor as therapeutic agents in cardiovascular and related diseases.