O-glycan structures in apo(a) subunit of human lipoprotein(a) suppresses the pro-angiogenic activity of galectin-1 on human umbilical vein endothelial cells.

Apolipoprotein(a) [apo(a)] is a highly polymorphic O-glycoprotein circulating in human plasma as lipoprotein(a) [Lp(a)]. The O-glycan structures of apo(a) subunit of Lp(a) serve as strong ligands of galectin-1, an O-glycan binding pro-angiogenic lectin abundantly expressed in placental vascular tissues. But the pathophysiological significance of apo(a)-galectin-1 binding is not yet been revealed.

Apolipoprotein(a), an enigmatic anti-angiogenic glycoprotein in human plasma: A curse or cure?

Angiogenesis is a finely co-ordinated, multi-step developmental process of the new vascular structure. Even though angiogenesis is regularly occurring in physiological events such as embryogenesis, in adults, it is restricted to specific tissue sites where rapid cell-turnover and membrane synthesis occurs. Both excessive and insufficient angiogenesis lead to vascular disorders such as cancer, ocular diseases, diabetic retinopathy, atherosclerosis, intra-uterine growth restriction, ischemic heart disease, stroke etc.

Activity of MUC1 cancer antigen-binding plasma anti-α-galactoside antibody correlates inversely with size of autologous lipoprotein(a).

Variation in ligand-binding affinity of natural plasma anti-α-galactoside antibody (anti-Gal) is a plausible reason for differing anti-cancer defense among individuals since serine- and threonine-rich peptide sequences (STPS) in the cancer-specific MUC-1 antigen are surrogate ligands for this antibody. As affinity of a natural antibody could be modulated by systemic antigens by processes including affinity maturation, we examined the contribution of the size of lipoprotein(a) [Lp(a)], an efficient autologous anti-Gal-binding macromolecule that possesses variable numbers of STPS due to genetically determined size polymorphism, towards the specific activity (activity per unit mass) of anti-Gal. Binding of purified Lp(a) to FITC-labeled anti-Gal, measured in terms of increase in fluorescence of the latter, was inhibited by LDL in proportion to Lp(a) size presumably because LDL molecules also bind noncovalently and in proportion to Lp(a) size at the O-glycosylated and STPS-rich region of Lp(a).

Circulating Lp(a):LDL complexes contain LDL molecules proportionate to Lp(a) size and bind to galectin-1: a possible route for LDL entry into cells.

The molecular mechanism of vascular pathology mediated by circulating lipoprotein(a) [Lp(a)] remains unknown. We examined the role of two distinguishing features of Lp(a) viz non-covalent complex formation with a low density lipoprotein (LDL) and heavy glycosylation as determinants of binding of this lipoprotein and its LDL complex to cell-surface receptors. LDL isolated from the Lp(a):LDL complex, free LDL and oxidized LDL were equally efficient in forming a reconstituted complex with pure Lp(a).

Human plasma anti-α-galactoside antibody forms immune complex with autologous lipoprotein(a).

Anti-α-galactoside antibody (anti-Gal) from human plasma that bound to α-galactoside-bearing guar galactomannan gel and was eluted with specific sugar (affinity-purified anti-Gal ; APAG) invariably contained apo(a) and apo B subunits in a proportion close to that in plasma lipoprotein(a) [Lp(a)]. Since LDL does not contain apo(a), result suggested Lp(a) as a component of APAG. Lp(a) in APAG was complexed with anti-Gal since plate-coated anti-apo(a) captured Lp(a) along with the antibody.