title: Apolipoprotein(a) enhances platelet responses to the thrombin receptor-activating peptide SFLLRN.
abstract: Elevated levels of lipoprotein(a) [Lp(a)] are correlated with an increased risk of atherosclerotic disease. We examined the effect of recombinant apolipoprotein(a) [r-apo(a)] and Lp(a) on responses of washed human platelets, prelabeled in the dense granules with [14C]serotonin and suspended in Tyrode's solution, to ADP and the thrombin receptor-activating peptide SFLLRN. No effect of the 17 kringle (K), 12K, or 6K r-apo(a) derivatives (at concentrations of 0.35 and 0.7 micromol/L) or Lp(a) (up to 0.1 micromol/L) on primary ADP-induced platelet aggregation was observed. In contrast, weak platelet responses stimulated by 7.5 micromol/L SFLLRN were significantly enhanced by the r-apo(a) derivatives; eg, 0.7 micromol/L 17K r-apo(a) increased aggregation from 15+/-4% to 58+/-6%, release of [14C]serotonin from 9+/-3% to 36+/-6%, and formation of thromboxane A2, measured as its stable metabolite thromboxane B2, from 7+/-1 to 29+/-5 ng/10(9) platelets (n=3; P<0.04 to 0.015). Significant enhancement of aggregation and release of granule contents was observed at a concentration of 17K r-apo(a) as low as 0.175 micromol/L. Purified Lp(a) (0.25 to 0.1 micromol/L) also enhanced SFLLRN-induced aggregation and release in a dose-dependent manner. Although plasminogen (0.7 and 1.5 micromol/L) and low density lipoprotein (0.025 to 0.1 micromol/L) both exhibited potentiating effects on SFLLRN-mediated platelet aggregation, the magnitude of the responses was less than that observed with either the r-apo(a) derivatives or Lp(a). The enhanced responses of platelets via the protease-activated receptor- thrombin receptor in the presence of Lp(a) may contribute to the increased risk of thromboembolic complications of atherosclerosis associated with this lipoprotein.
authors.affiliation: Department of Biochemistry, University of Toronto, Ontario, Canada. margaret.rand@sickkids.on.ca
authors.forename: M L
authors.initials: ML
authors.lastname: Rand
authors.forename: W
authors.initials: W
authors.lastname: Sangrar
authors.forename: M A
authors.initials: MA
authors.lastname: Hancock
authors.forename: D M
authors.initials: DM
authors.lastname: Taylor
authors.forename: S M
authors.initials: SM
authors.lastname: Marcovina
authors.forename: M A
authors.initials: MA
authors.lastname: Packham
authors.forename: M L
authors.initials: ML
authors.lastname: Koschinsky
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D001054:Apolipoproteins A / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D002460:Cell Line; D004622:Embryo, Mammalian; D006801:Humans; D007668:Kidney; D010446:Peptide Fragments / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D018179:Receptors, Thrombin / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D001054:Apolipoproteins A; D010446:Peptide Fragments; D018179:Receptors, Thrombin; D011994:Recombinant Proteins; C082835:thrombin receptor peptide (42-47); D000244:Adenosine Diphosphate