Resolvin E1 Has Selective and Potent Actions on Human Platelets

Introduction: Periodontal disease induced by bacterial infection is a chronic inflammatory disease that has been linked to the occurrence of cardiovascular diseases and thrombus formation. It is well-appreciated that diets rich in omega-3 fish oils reduce the risk of coronary events, but the mechanisms responsible have yet to be elucidated. Resolvins are bioactive enzymatic products endogenously synthesized from omega-3 fatty acids that possess potent anti-inflammatory and pro-resolving actions.

Objective: Since platelet aggregation and thrombus formation are central in the pathogenesis of cardiovascular disease, the actions of resolvins on agonist stimulated platelet aggregation were investigated.

Methods: Platelet rich plasma (PRP) and platelets were isolated from healthy human volunteers. PRP was first incubated (15 min, 37°C) with Resolvin E1 (RvE1), Δ6, 14-trans RvE1, chemerin, a peptide ligand for ChemR23, or vehicle prior to addition 10uM ADP, 1.5 µg/mL collagen or 0.5µM U46619. Platelet aggregation was monitored by changes in light transmittance of stirred (400 rpm) PRP using a dual channel aggregometer. FACS analysis was performed to detect surface expression of ChemR23, a receptor for RvE1. Statistical significance was assessed by 2-tailed Student's t test.

Results: RvE1 (1nM-1µM) selectively blocked platelet aggregation. In human platelet-rich plasma, RvE1 blocked ADP-stimulated platelet aggregation in a concentration dependent manner (IC50 ~10nM, n=6). In comparison, RvE1 blocked thromboxane receptor agonist U46619-induced (n=6) but not collagen-stimulated (n=3) aggregation. A biologically inactive isomer, Δ6,14-trans-RvE1 (100nM, n=3), did not block ADP-stimulated aggregation. Inhibition of ADP-stimulated platelet aggregation was not further enhanced with aspirin treatment. ChemR23 was expressed on both human megakaryocytes and isolated human platelets. Chemerin also inhibited ADP-stimulated platelet aggregation at micromolar concentrations.

Conclusion: RvE1 demonstrates potent anti-platelet actions that may underlie the beneficial actions of the omega-3 fatty acids such as EPA in humans, specifically those associated with cardiovascular diseases. (Supported by NIH GM38765, DK074448 and P50-DE016191).