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, Susan S. Smyth

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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 in response 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 "nonrespon- siveness" may be related to heightened platelet expression of LPA receptor 4 and PPARγ. 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. Conclusion: Platelet LPA signaling may involve stimulatory and inhibitory pathways, with the inhibitory pathway predominating in ≈20% of individuals. Diseases such as CAD that affect platelet reactivity may attenuate this inhibitory pathway in platelets.

Original languageEnglish
Pages (from-to)555-561
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number3
DOIs
StatePublished - Mar 1 2008

Keywords

  • Coronary artery disease
  • Lysophosphatidic acid
  • Platelet activation
  • Platelet aggregation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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