Apolipoprotein (a) impairs endothelial progenitor cell-mediated angiogenesis.

Improvement of blood flow and promotion of angiogenesis are important therapeutic measures for the treatment of ischemic peripheral vascular diseases. Since apolipoprotein (a) (apo (a)) is a glycoprotein with repetitive kringle domains exhibiting 75% to 98% structural homology with plasminogen (Plg), apo (a) may also have a negative effect on endothelial progenitor cell (EPC)-induced angiogenesis through Plg-like inhibitory effects on EPC proliferation, adhesion, migration, and angiogenesis. To evaluate the effect of apo (a) on EPCs-induced angiogenesis, EPCs were isolated from the bone marrow of apo (a) transgenic mice, wild-type litter mates, and normal mice. These cells were cultured without or with apo (a) before transplantation. Hindlimb ischemia models were surgically induced in mice, which then received an intravenous injection of 3×10(5) EPCs. At 3, 7, and 14 days post EPC transplantation, the adhesion, migration abilities, and capillary density in calf muscles were assessed. Results indicate that apo (a) significantly reduced the adhesion and migration abilities of EPCs. Furthermore, the tubule-like formation of EPCs on Matrigel gels was damaged. In vivo experiments showed the homing of EPCs to ischemic peripheral vascular, and the number of capillary vessels decreased significantly in apo(a) transgenic mice. This study demonstrated that apo (a) could attenuate the adhesion, migration, and homing abilities of EPCs and could impair the angiogenesis ability of EPCs.

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

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 ß-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/ß-catenin complexes in a Src-dependent manner, decreased ß-catenin phosphorylation, and increased phosphorylation of Akt and glycogen synthase kinase-3ß, ultimately resulting in increased nuclear translocation of ß-catenin; all of these effects are downstream of apo(a) attenuation of phosphatase and tensin homologue deleted on chromosome 10 activity. The ß-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.

A novel peptide from human apolipoprotein(a) inhibits angiogenesis and tumor growth by targeting c-Src phosphorylation in VEGF-induced human umbilical endothelial cells.

Many angiogenesis inhibitors are derived from large plasma proteins. Previous studies showed that the Kringle5-like domain (termed KV) in human apolipoprotein (a) is a potential antiangiogenic factor. However, its active region and the underling molecular mechanism remain elusive. Here, we identified an 11-amino acid peptide (named KV11) as the key region for the antiangiogenic function of the KV domain of apolipoprotein (a). We demonstrate that KV11 inhibits angiogenesis in vitro by suppressing human umbilical vein endothelial cell migration and microtubule formation. KV11 inhibits angiogenesis in chicken chorioallantoic membrane assays and mouse corneal micropocket angiogenesis assays in vivo. KV11 peptide shows no effect on tumor cell growth or proliferation, but significantly inhibits tumor growth in SCID mouse xenograft tumor model (p < 0.01) by preventing tumor angiogenesis. We elucidate that KV11 peptide suppresses angiogenesis and tumor progression by targeting the c-Src/ERK signaling pathways. Together, these studies provide the first evidence that KV11 from apolipoprotein KV domain has anti-angiogenesis functions and may be an anti-tumor drug candidate.