Inhibition of plasminogen activation by lipoprotein(a)

Elevated plasma levels of lipoprotein(a) (Lp(a)) are a risk factor for various disease states including heart attack and stroke. Lp(a) may provide a vital link between atherosclerosis and thrombosis due to its similarity to the fibrinolytic plasma zymogen plasminogen. It is hypothesized that the apolipoprotein(a) (apo(a)) moiety of Lp(a) inhibits the activation of plasminogen to plasmin, thereby attenuating fibrinolysis and generating a hypercoaguable state in vivo.;Fluorescence-based studies examined the effect of Lp(a) on Glu 1-/Lys78-plasminogen activation in the presence of both native and degraded fibrin cofactors. Apo(a) domains KIV1--4 , KIV10, and KV were important for the inhibition of Glu1 plasminogen activation, whereas apo(a) failed to inhibit Lys78-plasminogen activation. The kinetic data conformed to a single, equilibrium template model in which apo(a) can bind to plasminogen, tissue-type plasminogen activator, and/or cofactor---an important paradigm shift from the traditional viewpoint that apo(a) only competes with plasminogen for binding sites on fibrin. Surface plasmon resonance (SPR) studies further examined the binary interaction between plasminogen and apo(a) in real-time. Native Glu1-plasminogen bound to apo(a) with high-affinity, whereas a series of elastase- and plasmin-derived plasminogen fragments did not. The novel observation was made that lysine residues on both plasminogen and apo(a) are important for mediating binding between the two proteins. The SPR data also indicated that a conformational change in the plasminogen-apo(a) complex may occur after the initial binding event.;Overall, the increased atherosclerotic/thrombotic risk associated with elevated Lp(a) levels in vivo may result from the formation of quaternary complexes (cofactor + tissue-type plasminogen activator + plasminogen + apo(a)) that exhibit decreased plasmin generation. Differential binding kinetics between Glu1-/Lys78-plasminogen and apo(a) may also explain why Lp(a) is a strong inhibitor of fibrinolysis at the onset (i.e. when Glu1-plasminogen predominates), yet a poor inhibitor as the fibrinolytic process proceeds (i.e. when Lys78-plasminogen predominates). Continued investigations to examine how apo(a) and the fibrinolytic system components interact with one another are necessary to understand the role of Lp(a) in health and disease.