Fractalkine activates a signal transduction pathway similar to P2Y12 and is associated with impaired clopidogrel responsiveness.
OBJECTIVE
Fractalkine (FKN) activates a G(αi) protein-coupled signaling pathway similar to the one activated by ADP via P2Y(12), which is the drug target of clopidogrel. FKN levels are increased under several disease conditions associated with impaired clopidogrel responsiveness.


RESULTS
Blood samples were obtained from healthy volunteers and from 40 patients under chronic clopidogrel treatment. FKN reduced prostaglandin E1-induced vasodilator-stimulated phosphoprotein phosphorylation by ≈ 25% (P<0.01) at least partially mimicking the effect of ADP via P2Y(12). In vitro, FKN increased platelet reactivity index in clopidogrel-treated patients indicating potential activation of downstream targets of P2Y(12). When stratifying patients by their FKN levels, patients within the highest quartile of FKN (2042 ± 25 pg/mL) had the weakest response to clopidogrel (platelet reactivity index, 68 ± 4%), and patients within the lowest quartile (479 ± 50 pg/mL) had the strongest response (platelet reactivity index, 48 ± 7%; P=0.0106). FKN by itself induced phosphoinositide 3-kinase activation leading to Akt phosphorylation at Ser(473) (P<0.01 versus basal).


CONCLUSIONS
In addition to desensitizing platelets to prostaglandin E1 via G(αi), FKN induces phosphoinositide 3-kinase-dependent Akt phosphorylation via a G(βγ) protein similar to ADP signaling through P2Y(12). FKN increased the platelet ADP response in clopidogrel-treated patients. Once released from an atherosclerotic lesion, this mechanism could contribute locally to impaired clopidogrel responsiveness at the vulnerable plaque.
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Ulrike
U
Flierl
Daniela
D
Fraccarollo
Eva
E
Lausenmeyer
Tim
T
Rosenstock
Christian
C
Schulz
Steffen
S
Massberg
Johann
J
Bauersachs
Andreas
A
Schäfer
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D054428:Chemokine CX3CL1 / Q000097:blood / Q000502:physiology*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D058925:Receptors, Purinergic P2Y12 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D019869:Phosphatidylinositol 3-Kinases; D000527:Alprostadil; D013988:Ticlopidine