Enzymatic and chemical modifications of lipoprotein(a) selectively alter its lysine-binding functions.
The pathogenicity of lipoprotein(a) [Lp(a)] as a risk factor for cardiovascular disease may depend upon its lysine binding sites (LBS) which impart unique functions to Lp(a) not shared with low density lipoprotein. Biologically relevant modifications of Lp(a) were tested for alterations of LBS activity using two previously described functional assays, a LBS-Lp(a) immunoassay and a lysine-Sepharose bead assay. In the LBS-Lp(a) immunoassay, minimal changes in the LBS activity of Lp(a) were observed after modification with lipoprotein lipase, sphingomyelinase, or phospholipase C. In contrast, a significant (p<0.003) increase in the LBS activity of Lp(a) occurred after phospholipase A2 (PLA2) treatment, and this increase was confirmed using the lysine-Sepharose bead assay. The increase depended upon the release of fatty acids from Lp(a) by PLA2. A decrease in the LBS activity of Lp(a) occurred after oxidation of Lp(a) with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) (44% decrease), but CuSO4 oxidation increased LBS activity (210%). N-acetylcysteine (NAC) treatment of Lp(a) decreased (48%) LBS activity while homocysteine treatment had no (89%) effect. Thus, modification of phospholipids and protein moieties can alter the LBS-activity of Lp(a). Such enzymatic and chemical modifications may contribute to the variability in LBS function of Lp(a) seen within the population.
Hoover-Plow
J
J
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, FF20, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. hooverj@cesmtp.ccf.org
Skocir
P
P
D000111:Acetylcysteine / Q000494:pharmacology; D000578:Amidines / Q000494:pharmacology; D001665:Binding Sites; D002846:Chromatography, Affinity; D019327:Copper Sulfate / Q000494:pharmacology; D006710:Homocysteine / Q000494:pharmacology; D007118:Immunoassay; D017270:Lipoprotein(a) / Q000187:drug effects / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D010084:Oxidation-Reduction; D010741:Phospholipases A / Q000494:pharmacology; D054467:Phospholipases A2
D000578:Amidines; D017270:Lipoprotein(a); D006710:Homocysteine; C046728:2,2'-azobis(2-amidinopropane); D010741:Phospholipases A; D054467:Phospholipases A2; D008239:Lysine; D019327:Copper Sulfate; D000111:Acetylcysteine