title: Apolipoprotein(a) stimulates nuclear translocation of β-catenin: a novel pathogenic mechanism for lipoprotein(a).
abstract: 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 β-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/β-catenin complexes in a Src-dependent manner, decreased β-catenin phosphorylation, and increased phosphorylation of Akt and glycogen synthase kinase-3β, ultimately resulting in increased nuclear translocation of β-catenin; all of these effects are downstream of apo(a) attenuation of phosphatase and tensin homologue deleted on chromosome 10 activity. The β-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.
authors.affiliation: Department of Biochemistry, Queen's University, Kingston, ON, Canada.
authors.forename: Taewoo
authors.initials: T
authors.lastname: Cho
authors.forename: Rocco
authors.initials: R
authors.lastname: Romagnuolo
authors.forename: Corey
authors.initials: C
authors.lastname: Scipione
authors.forename: Michael B
authors.initials: MB
authors.lastname: Boffa
authors.forename: Marlys L
authors.initials: ML
authors.lastname: Koschinsky
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D053241:Apoprotein(a) / Q000502:physiology*; D050197:Atherosclerosis / Q000378:metabolism; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004790:Enzyme Induction; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010958:Plasminogen / Q000502:physiology; D011485:Protein Binding; D020033:Protein Isoforms / Q000502:physiology; D021381:Protein Transport; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D053241:Apoprotein(a); D015820:Cadherins; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D018836:Inflammation Mediators; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010958:Plasminogen; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; D000099152:Cadherin 5; C496540:PTGS2 protein, human; C494929:PTEN protein, human