Apolipoprotein(a) stimulates nuclear translocation of beta-catenin: a novel pathogenic mechanism for lipoprotein(a)

作者：Cho Taewoo; Romagnuolo Rocco; Scipione Corey; Boffa Michael B; Koschinsky Marlys L^*

来源：Molecular Biology of the Cell, 2013, 24(3): 210-221.

DOI：10.1091/mbc.E12-08-0637

Lipoprotein(a) (Lp(a)) is associated with cardiovascular disease risk. This may be attributable to the ability of Lp(a) to elicit endothelial dysfunction. We previously reported that apolipoprotein(a) (apo(a); the distinguishing kringle-containing component of Lp(a)) elicits cytoskeletal rearrangements in vascular endothelial cells, resulting in increased cellular permeability. These effects require a strong lysine-binding site (LBS) in apo(a). We now report that apo(a) induces both nuclear beta-catenin-mediated cyclooxygenase-2 (COX-2) expression and prostaglandin E2 secretion, indicating a proinflammatory role for Lp(a). Apo(a) caused the disruption of VE-cadherin/beta-catenin complexes in a Src-dependent manner, decreased beta-catenin phosphorylation, and increased phosphorylation of Akt and glycogen synthase kinase 3 beta, ultimately resulting in increased nuclear translocation of beta-catenin; all of these effects are downstream of apo(a) attenuation of phosphatase and tensin homologue deleted on chromosome 10 activity. The beta-catenin-mediated effects of apo(a) on COX-2 expression were absent using a mutant apo(a) lacking the strong LBS. Of interest, the normal and LBS mutant forms of apo(a) bound to human umbilical vein endothelial cells in a similar manner, and the binding of neither was affected by lysine analogues. Taken together, our findings suggest a novel mechanism by which apo(a) can induce proinflammatory and proatherosclerotic effects through modulation of vascular endothelial cell function.

• 出版日期2013-2-1