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Arteriosclerosis, Thrombosis, and Vascular Biology
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Published Online
on January 17, 2008

Arteriosclerosis, Thrombosis, and Vascular Biology. 2008
Published online before print January 17, 2008, doi: 10.1161/ATVBAHA.107.151837
A more recent version of this article appeared on March 1, 2008
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*Compound via MeSH
*Substance via MeSH

Submitted on August 7, 2007
Accepted on December 23, 2007

Individual Heterogeneity in Platelet Response to Lysophosphatidic Acid. Evidence for a Novel Inhibitory Pathway

Zehra Pamuklar ; Jin Sun Lee ; Hsin-Yuan Cheng ; Manikandan Panchatcharam ; Steve Steinhubl ; Andrew J. Morris ; Richard Charnigo ; and Susan S. Smyth *

From the Division of Cardiovascular Medicine (Z.P., H.-Y.C., M.P., S.S., A.J.M., R.C., S.S.), The Gill Heart Institute, University of Kentucky, Lexington; the School of Medicine (J.S.L.), The University of North Carolina at Chapel Hill; and the Department of Biostatistics (R.C.), College of Public Health, University of Kentucky, Lexington.

* To whom correspondence should be addressed. E-mail: susansmyth{at}uky.edu.

Objective—The bioactive lipid lysophosphatidic acid (LPA) stimulates platelet actin reorganization, adhesion, shape change, and aggregation. LPA is present in blood and exposure or release of LPA after atherosclerotic plaque rupture has been proposed to trigger platelet thrombus formation.

Methods and Results—In this report, we characterize heterogeneity in LPA responses among individuals. Platelets isolated from approximately 20% of healthy donors consistently failed to aggregate to LPA. Our studies indicate that, rather than lacking stimulatory pathways, platelets from "nonresponsive" donors respond to LPA by triggering inhibitory pathway(s) to block platelet aggregation. Consistent with this observation, LPA-induced aggregation could be partially restored to "nonresponsive" platelets by pharmacological inhibition of cAMP generation. LPA "nonresponsiveness" may be related to heightened platelet expression of LPA receptor 4 and PPAR{gamma}. Among 70 patients with stable coronary artery disease (CAD), only 1 (1.4%) was identified as an LPA nonresponder. Moreover, in 33 patients presenting for diagnostic catheterization, CAD was identified as having a bivariate association with platelet LPA responder/nonresponder status.

Conclusions—Platelet LPA signaling may involve stimulatory and inhibitory pathways, with the inhibitory pathway predominating in {approx}20% of individuals. Diseases such as CAD that affect platelet reactivity may attenuate this inhibitory pathway in platelets.
Key words: platelet aggregation • platelet activation • lysophosphatidic acid • coronary artery disease






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