title: The apolipoprotein(a) component of lipoprotein(a) stimulates actin stress fiber formation and loss of cell-cell contact in cultured endothelial cells.
abstract: 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.
authors.affiliation: Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Pellegrino
authors.forename: Emilia
authors.initials: E
authors.lastname: Furmaniak-Kazmierczak
authors.forename: Justin C
authors.initials: JC
authors.lastname: LeBlanc
authors.forename: Taewoo
authors.initials: T
authors.lastname: Cho
authors.forename: Kathy
authors.initials: K
authors.lastname: Cao
authors.forename: Santica M
authors.initials: SM
authors.lastname: Marcovina
authors.forename: Michael B
authors.initials: MB
authors.lastname: Boffa
authors.forename: Graham P
authors.initials: GP
authors.lastname: Côté
authors.forename: Marlys L
authors.initials: ML
authors.lastname: Koschinsky
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism; D000199:Actins / Q000737:chemistry* / Q000378:metabolism; D000209:Acute-Phase Proteins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D015703:Antigens, CD; D001054:Apolipoproteins A / Q000737:chemistry*; D017209:Apoptosis; D001905:Botulinum Toxins / Q000378:metabolism; D015820:Cadherins; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D004591:Electrophoresis, Polyacrylamide Gel; D042783:Endothelial Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D018994:Myosin Light Chains; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D022502:Stress Fibers; D013997:Time Factors; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D000099152:Cadherin 5
chemical_list: D036002:ADP Ribose Transferases; D000199:Actins; D000209:Acute-Phase Proteins; D000577:Amides; D015703:Antigens, CD; D001054:Apolipoproteins A; D001905:Botulinum Toxins; D015820:Cadherins; D002118:Calcium; D004791:Enzyme Inhibitors; D018994:Myosin Light Chains; D011725:Pyridines; D000099152:Cadherin 5; C010781:acute-phase protein rho; C108830:Y 27632; C063007:exoenzyme C3, Clostridium botulinum