Resolvin E1 regulates adenosine diphosphate activation of human platelets.
OBJECTIVE
To investigate the ability of resolvin E1 (RvE1) to regulate adenosine diphosphate (ADP) activation of platelets via specific receptors because RvE1 reduces platelet aggregation with certain agonists, including ADP.


RESULTS
RvE1 is an eicosapentaenoic acid-derived specialized proresolving mediator generated during the resolution of acute inflammation. RvE1 exhibits potent organ-protective actions in vivo and acts on specific cell types, including platelets. RvE1, 0.1 to 100 nmol/L, incubated with platelets gave reduced ADP-stimulated P-selectin mobilization (IC(50), approximately 1.6×10(-12) mol/L) and polymerized actin content compared with control platelets. RvE1, 1 to 100 nmol/L, did not stimulate or block intracellular Ca(2+) mobilization. By using a new P2Y(12)-β-arrestin-coupled cell system, ADP-activated P2Y(12) with an EC(50) of 5×10(-6) mol/L and RvE1 did not directly stimulate P2Y(12) or block the ADP-P2Y(12) signals. In this system, another eicosanoid, leukotriene E(4) (LTE(4)) (EC(50), 1.3×10(-11) mol/L), dose dependently activated P2Y(12). When recombinant P2Y(12)-expressing cells were transiently transfected with an RvE1 receptor, human ChemR23 (present on human platelets), with the addition of RvE1 (0.1-10.0 nmol/L), blocked ADP signals (IC(50), approximately 1.6×10(-11) mol/L) in P2Y(12)-ChemR23-expressing cells compared with mock transfections.


CONCLUSIONS
RvE1's regulatory actions (ie, reducing ADP-stimulated P-selectin mobilization and actin polymerization) are human (h)ChemR23-dependent. Moreover, specific platelet actions of RvE1 selectively engaged with ADP-activated platelets that illuminate a new cellular mechanism and affect ω-3 eicosapentaenoic acid, which may contribute to both resolution of vascular inflammation and ADP-dependent platelet activation relevant in pathological cardiovascular events.
Fredman
Gabrielle
G
Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Center for Experimental Therapeutics and Reperfusion Injury, Boston, Mass 02115, USA.
Van Dyke
Thomas E
TE
Serhan
Charles N
CN
D000199:Actins / Q000097:blood / Q000737:chemistry; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002118:Calcium / Q000097:blood; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers / Q000235:genetics; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000097:blood / Q000494:pharmacology; D008954:Models, Biological; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D055503:Protein Multimerization; D019707:Receptors, Chemokine / Q000097:blood / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000097:blood / Q000235:genetics; D058925:Receptors, Purinergic P2Y12; D011994:Recombinant Proteins / Q000097:blood / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection
D000199:Actins; C102741:CMKLR1 protein, human; D017931:DNA Primers; D018836:Inflammation Mediators; D019007:P-Selectin; C548576:P2RY12 protein, human; D019707:Receptors, Chemokine; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D011994:Recombinant Proteins; D000244:Adenosine Diphosphate; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid; D002118:Calcium