APOC3(Arrakis)

Apolipoprotein C3 (apoC3) circulates primarily on triglyceride-rich lipoproteins and promotes atherosclerosis by fostering lipidemia and inflammation. Thus, apoC3 represents an important cardiovascular risk factor and is associated with cardiovascular events and mortality. Due to their dual nature as hemostatic and immunomodulatory effector cells, platelets play an important role in development and progression of atherosclerosis and are responsible for thrombotic/thromboembolic events upon plaque rupture.

We aimed to elucidate the impact of apoC3 on pro-thrombotic platelet functions.

Platelets were isolated from healthy volunteers and the effect of apoC3 on their activation and aggregation was assessed by flow cytometry, ELISA, light transmission and multiple electrode aggregometry. Platelet spreading and cytoskeletal remodeling were examined by immunofluorescence microscopy. In vivo relevance was confirmed in a murine model of FeCl₃-induced thrombosis.

ApoC3 strongly reduced platelet aggregation independently of the presence of plasma or other blood cells and impaired both αIIbβ3 activation and degranulation. While agonist-induced calcium mobilization, hyperpolarization and membrane fluidity were not affected, apoC3 slightly reduced AKT phosphorylation and increased VASP phosphorylation. Further, apoC3-treated platelets displayed impaired lamellipodia formation, which was accompanied by aberrant actin cytoskeleton remodeling. Finally, transfusion of apoC3-treated platelets into mice delayed thrombus formation in vivo.

We identified apoC3 as lipoprotein-derived inhibitor of pro-thrombotic platelet functions, mediating anti-aggregatory effects likely via modulating AKT and VASP signaling and interfering with actin cytoskeleton remodeling to impair lamellipodia formation. Thus, apoC3 may counterbalance its pro-atherogenic properties on lipid metabolism and inflammation by dampening thrombotic risk in hyperlipidemia.