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Apolipoprotein(a), through Its Strong Lysine-binding Site in KIV10, Mediates Increased Endothelial Cell Contraction and Permeability via a Rho/Rho Kinase/MYPT1-dependent Pathway*

By Taewoo Cho, Yoojin Jung and Marlys L. Koschinsky

Abstract

Substantial evidence indicates that endothelial dysfunction plays a critical role in atherogenesis. We previously demonstrated that apolipoprotein(a) (apo(a); the distinguishing protein component of the atherothrombotic risk factor lipoprotein(a)) elicits rearrangement of the actin cytoskeleton in human umbilical vein endothelial cells, characterized by increased myosin light chain (MLC) phosphorylation via a Rho/Rho kinase-dependent signaling pathway. Apo(a) contains kringle (K)IV and KV domains similar to those in plasminogen: apo(a) contains 10 types of plasminogen KIV-like sequences, followed by sequences homologous to the plasminogen KV and protease domains. Several of the apo(a) kringles contain lysine-binding sites (LBS) that have been proposed to contribute to the pathogenicity of Lp(a). Here we demonstrate that apo(a)-induced endothelial barrier dysfunction is mediated via a Rho/Rho kinase-dependent signaling pathway that results in increased MYPT1 phosphorylation and hence decreased MLC phosphatase activity, thus leading to an increase in MLC phosphorylation, stress fiber formation, cell contraction, and permeability. In addition, studies using recombinant apo(a) variants indicated that these effects of apo(a) are dependent on sequences within the C-terminal half of the apo(a) molecule, specifically, the strong LBS in KIV10. In parallel experiments, the apo(a)-induced effects were completely abolished by treatment of the cells with the lysine analogue ε-aminocaproic acid and the Rho kinase inhibitor Y27632. Taken together, our findings indicate that the strong LBS in apo(a) KIV10 mediates all of our observed effects of apo(a) on human umbilical vein endothelial cell barrier dysfunction. Studies are ongoing to further dissect the molecular basis of these findings

Topics: Lipids and Lipoproteins: Metabolism, Regulation, and Signaling
Publisher: American Society for Biochemistry and Molecular Biology
OAI identifier: oai:pubmedcentral.nih.gov:2662143
Provided by: PubMed Central
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