Inhibitors for the In Vitro Assembly of Lp(a)

Author:

Frank Sasa1,Durovic Srdan1,Kostner Karam1,Kostner Gert M.1

Affiliation:

1. From the Medical Biochemistry Department, University of Graz, and the Second Department of Medicine, University Hospital of Vienna (Austria) (K.K.).

Abstract

Abstract Lp(a) is composed of an LDL-like core and the glycoprotein apo(a). Current evidence strongly suggests that the assembly of this atherogenic lipoprotein proceeds outside the liver cells in a two-step fashion. In the first step, a loose complex is formed involving kringle-4 motifs in apo(a) and one or more Lys side chains in apoB-100. In the second step, this complex is stabilized by a disulfide bridge. Indications are that Lp(a) assembly is critical in the determination of plasma apo(a) concentrations. Therefore, we searched for substances that interfere with the first step of Lp(a) assembly. ε-Aminohexoic acid (ε-AHA), known as an inhibitor from earlier assembly studies, had an IC 50 of 4.8 mmol/L. The IC 50 of Pro, HO-p-aminobenzene sulfonamide, Lys, N -ε-acetyl-Lys, taurine, Glu, serotonin, and benzamidine were all >20 mmol/L. γ-Aminobutyric acid, spermine, and spermidine exhibited IC 50 on the same order of magnitude as ε-AHA. The substances with the highest inhibitory action were tranexamic acid and δ-aminovaleric acid. Seven of eight patients treated in a pilot study with tranexamic acid (Cyclocapron) responded with a decrease of plasma apo(a) of 18.5±8.2%. We suggest that substances that interfere with the Lp(a) assembly are worth pursuing further for their usefulness as therapeutic agents in reducing high plasma Lp(a) concentrations.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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