L-4F alters hyperlipidemic (but not healthy) mouse plasma to reduce platelet aggregation.
Background and Purpose- Hyperlipidemia is associated with platelet hyperreactivity. We hypothesized that L-4F, an apolipoprotein A-I mimetic peptide, would inhibit platelet aggregation in hyperlipidemic mice.


RESULTS
Injecting L-4F into apolipoprotein E (apoE)-null and low-density lipoprotein receptor-null mice resulted in a significant reduction in platelet aggregation in response to agonists; however, there was no reduction in platelet aggregation after injection of L-4F into wild-type (WT) mice. Consistent with these results, injection of L-4F into apoE-null mice prolonged bleeding time; the same result was not found in WT mice. Incubating L-4F in vitro with apoE-null platelet-rich plasma also resulted in decreased platelet aggregation. However, incubating washed platelets from either apoE-null or WT mice with L-4F did not alter aggregation. Compared with WT mice, unstimulated platelets from apoE-null mice contained significantly more 12-hydroxy 5,8,10,14-eicosatetraenoic acid, thromboxane A(2), and prostaglandins D(2) and E(2). In response to agonists, platelets from L-4F-treated apoE-null mice formed significantly less thromboxane A(2), prostaglandins D(2) and E(2), and 12-hydroxy 5,8,10,14-eicosatetraenoic acid.


CONCLUSIONS
By binding plasma-oxidized lipids that cause platelet hyperreactivity in hyperlipidemic mice, L-4F decreases platelet aggregation.
Buga
Georgette M
GM
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, Calif 90095-1679, USA. gbuga@mednet.ucla.edu
Navab
Mohamad
M
Imaizumi
Satoshi
S
Reddy
Srinivasa T
ST
Yekta
Babak
B
Hough
Greg
G
Chanslor
Shawn
S
Anantharamaiah
G M
GM
Fogelman
Alan M
AM
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000097:blood; D000244:Adenosine Diphosphate; D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D016718:Arachidonic Acid / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D003094:Collagen; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010979:Platelet Function Tests; D015230:Prostaglandin D2 / Q000097:blood; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013928:Thromboxane A2 / Q000097:blood
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; C472885:L-4F peptide; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D011973:Receptors, LDL; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000244:Adenosine Diphosphate; D003094:Collagen; D015232:Dinoprostone; D015230:Prostaglandin D2