Plaque Rupture, Lysophosphatidic Acid, and Thrombosis
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How does rupture of an atherosclerotic plaque activate platelets, and what can be done to lessen the risk of an ensuing thrombotic episode? Several important new observations that may provide answers to these vital questions are described by Rother et al1 in the present issue of Circulation. This group previously reported that lysophosphatidic acid (LPA), a phospholipid that activates platelets, is contained in the lipid-rich core of human atherosclerotic lesions.2 They now identify the molecular species of LPA present in the core of carotid artery plaques obtained from surgical specimens, demonstrate that lipid extracted from soft plaques can activate human platelets, and show that LPA receptor antagonists inhibit this process. Rother et al1 conclude that when a plaque ruptures, LPA contained in the exposed lipid sensitizes platelets to aggregating agents and thereby increases the thrombogenic potential. Furthermore, they suggest that LPA receptor antagonists will reduce the likelihood of thrombosis after plaque rupture. This is an interesting new approach that deserves careful consideration.
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Phospholipids and LPA
LPA is an intermediate in phospholipid metabolism that ordinarily is present in very small amounts in human plasma and tissues. It is a member of the lysophospholipid class of phospholipids. Lysophospholipids are formed by removal of 1 of the 2 fatty acid chains attached to the glycerol backbone of phosphoglycerides, the most abundant form of phospholipids. What makes LPA different from other lysophospholipids and gives it unique biochemical and functional properties is that it does not have a head group, such as choline or ethanolamine, attached to its phosphate moiety. Many cells can produce LPA and, in addition, have LPA receptors. Therefore, LPA can act as either an autocrine or paracrine mediator, and it is an important intracellular messenger that can affect many diverse biological processes.3
It is likely that 2 …