Editorial [Hot Topic: Targeting Arterial Thrombosis - Current Concepts and Future Developments (Guest Editor: Florian Krotz)]
Abstract:Myocardial infarction caused by thrombotic occlusion of a coronary artery represents the most dreaded complication of atherosclerotic disease. Conjoined with other forms of appearance of atherosclerotic vascular disease it represents one of the most important causes of mortality in the western civilization and is thus a major socio-economic problem.
The immediate thrombotic occlusion of a diseased vessel represents a complicated scenario spanning from rupture of an atherosclerotic plaque to the ultimate necrosis of the depending myocardial tissue. A sequelae of pathophysiological events take place within seconds of the development of vascular thrombosis, which include numerous triggering elicitors and mediators that support, augment or confine the several steps of primary and secondary hemostasis. Past years' scientific advances have further unraveled and helped to classify the roles of various agents that support arterial thrombosis and specified cellular signaling mechanisms, which put these actions into effect. In addition, it has become clear that the balance of vascular homeostatic small molecule mediators and the activation state of the cellular structure that is the crucial mediator of primary thrombotic occlusion - the anucleate platelet - may be the decisive determinants of fatal arterial occlusion.
This thematic issue of Current Drug Targets embraces fine review articles by scientific leaders in the field of platelet pathophysiology, vascular biology, and antithrombotic pharmacology. Their contributions comprise insights into new concepts derived from medicinal chemistry and pharmacology to recent experimental perceptions with potential clinical relevance. The composition of this issue is designed to provide the scientifically interested clinicians with important new information about evolving outstanding research concepts, and also provide the basic researcher with up-to-date reviews on emerging topics in vascular pathophysiology.
The first article of this issue by Essex and Li is a brilliant example of such an emerging scientific topic. Although platelet glycoprotein receptors like the fibrinogen receptor (GPIIb/IIIa) have long been known to be the most important mechanical mediators of platelet-platelet interaction, the molecular regulation of their redox-sensitive disulfite sites has not been understood so far. However, Essex and colleague nicely demonstrate, how redox state may form the basis for functionality of such glycoprotein receptors.
In close relation to redox state, free reactive oxidant or nitrogen species are increasingly recognized to dominate vascular homeostasis not only by regulating endothelial function, but also by modulating platelet signaling. The article by Tziros and Freedman explains why this has recently led to the development of new NO donors that attempt to enhance the antithrombotic actions of NO as a means to manipulate arterial thrombosis.
The articles by Shankar and colleagues and the review by Wee and Jackson further underline the integral role of platelets and their activatory signaling that form the basis for the development of more specific and highly effective antiplatelet agents. Based upon the finding that the P2Y12 receptor, the target of thienopyridine antiplatelet drugs like Clopidogrel, mediates its actions through G-protein dependent signaling, Shankar and colleagues have assembled an impressing overview of how several crucially important agonists like adenosine diphosphate (ADP), thrombin and thromboxane A2 (TXA2) activate platelets by acting via G-proteins and demonstrate how many of anti-thrombotic drugs mediate their beneficial effects by interfering with or preventing the initiation of the G-protein signaling pathway.
The crucial importance of specific signaling in platelet-dependent thrombosis is further being highlighted in the article by Wee and Jackson. For the first time, their contribution reviews in a most fascinating way, how tyrosine phosphorylation events regulate key signaling molecules that either stimulate signaling pathways in platelets, such as the collagen-dependent activation of glycoprotein GPVI, or are associated with regulatory pathways that limit the extent of platelet activation.
Lastly, the articles by Sohn and colleagues and the article by Klauss and Spannagl span a bridge from preclinical physiological knowledge to either clinical pathophysiology leading to myocardial infarction or to the development and first clinical experiences with a promising new antithrombotic class of drugs, which target at inhibiting the activated factor X or thrombin directly.
Document Type: Research Article
Affiliations: Cardiology, Medical Policlinic Ludwig-Maximilians-University Ziemssenstr.1, 80336 Munich Germany.
Publication date: October 1, 2006
More about this publication?
- Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.