Individual heterogeneity in platelet response to lysophosphatidic acid: evidence for a novel inhibitory pathway.
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.


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 "nonresponsiveness" may be related to heightened platelet expression of LPA receptor 4 and PPARgamma. 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 approximately 20% of individuals. Diseases such as CAD that affect platelet reactivity may attenuate this inhibitory pathway in platelets.
Pamuklar
Zehra
Z
Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY 40536, USA.
Lee
Jin Sun
JS
Cheng
Hsin-Yuan
HY
Panchatcharam
Manikandan
M
Steinhubl
Steve
S
Morris
Andrew J
AJ
Charnigo
Richard
R
Smyth
Susan S
SS
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D003327:Coronary Disease / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D016133:Polymerase Chain Reaction; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid