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J. Biol. Chem., Vol. 279, Issue 8, 6526-6533, February 20, 2004

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The Apolipoprotein(a) Component of Lipoprotein(a) Stimulates Actin Stress Fiber Formation and Loss of Cell-Cell Contact in Cultured Endothelial Cells^*

Mark Pellegrino, Emilia Furmaniak-Kazmierczak, Justin C. LeBlanc, Taewoo Cho, Kathy Cao, Santica M. Marcovina¶, Michael B. Boffa, Graham P. Côté, and Marlys L. Koschinsky, A career investigator of the Heart and Stroke Foundation of Ontario||

From the Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada and the ^¶Northwest Lipid Research Laboratories, University of Washington, Seattle, Washington 98103

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a risk factor for a variety of atherosclerotic disorders including coronary heart disease. In the current study, we report that incubation of cultured human umbilical vein or coronary artery endothelial cells with Lp(a) elicits a dramatic rearrangement of the actin cytoskeleton characterized by increased central stress fiber formation and redistribution of focal adhesions. These effects are mediated by the apolipoprotein(a) (apo(a)) component of Lp(a) since incubation of apo(a) with the cells evoked similar cytoskeletal rearrangements, while incubation with low density lipoprotein had no effect. Apo(a) also produced a time-dependent increase in transendothelial permeability. The cytoskeletal rearrangements evoked by apo(a) were abolished by C3 transferase, which inhibits Rho, and by Y-27632, an inhibitor of Rho kinase. In addition to actin cytoskeleton remodeling, apo(a) was found to cause VE-cadherin disruption and focal adhesion molecule reorganization in a Rho- and Rho kinase-dependent manner. Cell-cell contacts were found to be regulated by Rho and Rac but not Cdc42. Apo(a) caused a transient increase in the extent of myosin light chain phosphorylation. Finally apo(a) did not evoke increases in intracellular calcium levels, although the effects of apo(a) on the cytoskeleton were found to be calcium-dependent. We conclude that the apo(a) component of Lp(a) activates a Rho/Rho kinase-dependent intracellular signaling cascade that results in increased myosin light chain phosphorylation with attendant rearrangements of the actin cytoskeleton. We propose that the resultant increase in endothelial permeability caused by Lp(a) may help explain the atherosclerotic risk posed by elevated concentrations of this lipoprotein.

Received for publication, September 2, 2003 , and in revised form, November 20, 2003.

^* This work was supported in part by Heart and Stroke Foundation of Ontario Grants T4844 (to M. L. K.) and T4905 (to G. P. C.) and Program Grant HSPRG 4522. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a J. D. Schultz Summer Student Scholarship from the Heart and Stroke Foundation of Ontario.

^|| To whom correspondence should be addressed: Dept. of Biochemistry, Rm. A208 Botterell Hall, Queen's University, Kingston, Ontario K7L 3N6, Canada. Tel.: 613-533-6586; Fax: 613-533-2987; E-mail: mk11{at}post.queensu.ca.

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