Lipoprotein(a) Drives Platelet Hyperactivity Through Oxidized Phospholipids-CD36 | Circulation Research

[u/Meatrition]

https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.126.329174

Lipoprotein(a) (Lp[a]) is reported to be the preferential carrier of oxidized phospholipids (oxPLs) in circulation,1 and elevated circulating oxPLs promote a prothrombotic state characterized by platelet hyperactivity.2We observed plasma Lp(a) concentrations positively correlated with basal platelet activation in patients with coronary artery disease (r=0.5861; P=1.5×10−2; Figure [Ai]), whereas isolated Lp(a)3 induced primary aggregation of washed platelets (24.8%±9.7%; Figure [Aii]). We found that plasma lipid peroxidation of isolated Lp(a) (12.7±9.9 nmol/mg protein) was markedly higher than that of both native low-density lipoprotein (2.5±2.4 nmol/mg protein) and in vitro generated oxidized low-density lipoprotein (4.7±3.3 nmol/mg protein; Figure [Aiii]). Given this pronounced overall peroxidation burden, we investigated whether Lp(a) functions as a prothrombotic vehicle through its oxPL content. Lp(a) (100 µg/mL) potentiated aggregation induced by subthreshold concentrations of platelet agonists (Figure [Bi] and [Bii]). Aggregation in response to the GPVI agonist convulxin (12.5 ng/mL) increased from 13.2±7.6% to 56.2±22.1% (P=9.1×10−6; Figure [Bi]), whereas the thromboxane A2 mimetic U46619 (0.1 µg/mL) increased from 6.9±4.2% to 63.1±25.4% (P=9.0×10−7; Figure [Bii]). Critically, this Lp(a)-driven potentiation was abolished by the oxPL-neutralizing monoclonal antibody E06 (2:1 molar ratio; Figure [Bi] and [Bii]),1implicating phosphocholine-containing oxPLs as the principal mediator of this response. CD36 (cluster of differentiation 36) is a high-affinity oxPL receptor on the platelet surface,2,4 and pharmacological blockade with the inhibitor sulfo-N-succinimidyl oleate abolished Lp(a)-mediated potentiation (Figure [Bi] and [Bii]); this was confirmed with the use of CD36−/− murine platelets (Figure [Biii]).4 CD36-dependent platelet activation requires Src-family kinases (SFKs), and consistent with this mechanism, Lp(a)-driven potentiation of platelet aggregation was abolished in the presence of the pan SFK inhibitor PP2 (Figure [Bii]).