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 μmol/L) or Lp(a) (up to 0.1 μmol/L) on primary ADP-induced platelet aggregation was observed. In contrast, weak platelet responses stimulated by 7.5 μmol/L SFLLRN were significantly enhanced by the r-apo(a) derivatives; eg, 0.7 μmol/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/109 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 μmol/L. Purified Lp(a) (0.25 to 0.1 μmol/L) also enhanced SFLLRN-induced aggregation and release in a dose-dependent manner. Although plasminogen (0.7 and 1.5 μmol/L) and low density lipoprotein (0.025 to 0.1 μmol/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-1 thrombin receptor in the presence of Lp(a) may contribute to the increased risk of thromboembolic complications of atherosclerosis associated with this lipoprotein.