apyrase and Cardiovascular-Diseases

Thrombus formation at sites of disrupted atherosclerotic plaques is a leading cause of death and disability worldwide. Although the platelet is now recognized to be a central regulator of thrombus formation, development of antiplatelet reagents that selectively target thrombosis over hemostasis represents a challenge. Existing prophylactic antiplatelet therapies are centered on the use of aspirin, an irreversible cyclooxygenase inhibitor, and a thienopyridine such as clopidogrel, which inactivates the adenosine diphosphate-stimulated P2Y(12) receptor. Although these compounds are widely used and have beneficial effects for patients, their antithrombotic benefit is complicated by an elevated bleeding risk and substantial or partial "resistance." Moreover, combination therapy with these two drugs increases the hemorrhagic risk even further. This review explores the possibility of inhibiting the platelet-surface ionotropic P2X(1) receptor and/or elevating CD39/NTPDase1 activity as new therapeutic approaches to reduce overall platelet reactivity and recruitment of surrounding platelets at prothrombotic locations. Because both proteins affect platelet activation at an early stage in the events leading to thrombosis but are less crucial in hemostasis, they provide new strategies to widen the cardiovascular therapeutic window without compromising safety.

Topics: Adenosine Triphosphate; Antigens, CD; Apyrase; Aspirin; Biomedical Research; Cardiovascular Diseases; Cerebral Hemorrhage; Clinical Trials as Topic; Clopidogrel; Cyclooxygenase Inhibitors; Drug Therapy, Combination; Endothelium, Vascular; Humans; Myocardial Ischemia; Platelet Aggregation Inhibitors; Receptors, Purinergic P2; Receptors, Purinergic P2X; Receptors, Purinergic P2Y12; Ticlopidine; Treatment Outcome

The interaction between platelets and endothelium has been implicated in many disease processes. It is now known that platelets may be involved in the initiation of atheroma, modulate various inflammatory responses, and contribute to endothelial dysfunction, in addition to their classical role in thombosis. Indeed, various drugs targeting platelets and endothelium have been shown to be of benefit in disease states. The last few years has seen an exponential increase in our knowledge of platelet and endothelial biology. As a result of this, many new drugs, for example the ADP-antagonists and the GpIIbIIIa antagonists, have been developed for use in the clinical setting. There is also renewed interest in the use of older drugs (for example, the statins) in modulating platelet-endothelial interactions. This review focuses on the recent advances in our understanding of the interaction(s) between platelets and endothelium and how this knowledge could be manipulated for therapeutic gain.

Topics: Adenosine Triphosphatases; Antigens, CD; Apyrase; Blood Platelets; Cardiovascular Diseases; CD40 Ligand; Cell Adhesion; Chemokine CCL5; Cytokines; Endothelium, Vascular; Humans; Inflammation; Nitric Oxide; P-Selectin; Prostaglandins

Pathological circumstances like inflammation or ischemic insult facilitate the release of adenine nucleotides from several types of cells. These extracellular nucleotides are rapidly converted to adenosine by ectonucleotidases, mainly ectonucleoside triphosphate diphosphohydrolase1 (NTPDase1/CD39) and CD73. NTPDase1/CD39 can interact with caveolins, structural proteins of signal-transducing microdomains termed caveolae. Caveolins are thought to have physiological roles in heart ageing and cardiac diseases. The aim of this study was to investigate the expression of NTPDase1 together with caveolins in chronic human cardiovascular diseases and elucidate their role in human heart. The HPLC analysis showed significant increase in ATPase activity in pathological samples from patients with ischemic heart disease. Immunostaining also showed alterations in the expression and distribution of NTPDase1. Caveolin-1 and caveolin-2 expression was much alike in control and pathological cases, while expression of caveolin-3 was lower in pathological samples. Changes in the expression of NTPDase1 and caveolins seem to be independent of human cardiovascular disease.

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Adult; Aged; Antigens, CD; Apyrase; Cardiovascular Diseases; Caveolins; Fluorescent Antibody Technique; Humans; Hydrolysis; Immunohistochemistry; Middle Aged; Myocardium; Time Factors