Abstract 1612: L-4F Inhibits Platelet Aggregation and Prolongs Bleeding Time by Inhibiting the Formation of Arachidonic Acid Metabolites in Apo-E Null Mice
Hyperlipidemia is associated with both increased plasma levels of oxidized lipids and platelet hyper-reactivity. Since L-4F, an apoA-I mimetic peptide, reduces plasma levels of oxidized lipids, we hypothesized that it would inhibit platelet aggregation in hyperlipidemic mice. Platelets from apoE null mice that were incubated with L-4F showed a significant reduction in aggregation in response to collagen or ADP compared to vehicle control (p<0.001). Injection of L-4F into apoE null mice significantly inhibited platelet aggregation in response to arachidonic acid or collagen or ADP (p<0.01). Similarly, injection of L-4F into LDLR null mice fed an atherogenic diet significantly inhibited platelet aggregation in response to arachidonic acid (p=0.006) or collagen (p=0.003). A single L-4F injection significantly inhibited platelet aggregation for up to 72 hours (p<0.05) in apoE null mice. Compared to wild-type mice, unstimulated platelets from apoE null mice contained significantly more 12-HETE (p=0.033), thromboxane B2 (TXB2) (p=0.018), prostaglandins D2 (PGD2) (p=0.048) and E2 (PGE2) (p=0.036). In response to agonists, platelets from L-4F treated apoE null mice formed significantly less TXB2, PGD2, PGE2 and 12-HETE (p<0.05). L-4F treatment increased tail bleeding time in apoE null mice (p<0.0001) but not in wild-type mice, which had a slightly but significantly shorter bleeding time (p<0.05). Administration of aspirin significantly prolonged the tail bleeding time of both wild-type and apoE null mice (p<0.01). Injection of L-4F in aspirin treated mice did not further prolong the tail bleeding time. We conclude that L-4F improves platelet function in apoE null mice through pathways that are modulated by oxidized lipids which bind L-4F with very high affinity and likely include the COX-1 and 12-lipoxygenase pathways.