title: Apolipoprotein(a) acts as a chemorepellent to human vascular smooth muscle cells via integrin αVβ3 and RhoA/ROCK-mediated mechanisms.
abstract: Lipoprotein(a) (Lp(a)) is an independent risk factor for the development of cardiovascular disease. Vascular smooth muscle cell (SMC) motility and plasticity, functions that are influenced by environmental cues, are vital to adaptation and remodelling in vascular physiology and pathophysiology. Lp(a) is reportedly damaging to SMC function via unknown molecular mechanisms. Apolipoprotein(a) (apo(a)), a unique glycoprotein moiety of Lp(a), has been demonstrated as its active component. The aims of this study were to determine functional effects of recombinant apo(a) on human vascular SMC motility and explore the underlying mechanism(s). Exposure of SMC to apo(a) in migration assays induced a potent, concentration-dependent chemorepulsion that was RhoA and integrin αVβ3-dependent, but transforming growth factor β-independent. SMC manipulation through RhoA gene silencing, Rho kinase inhibition, statin pre-treatment, αVβ3 neutralising antibody and tyrosine kinase inhibition all markedly inhibited apo(a)-mediated SMC migration. Our data reveal unique and potent activities of apo(a) that may negatively influence SMC remodelling in cardiovascular disease. Circulating levels of Lp(a) are resistant to lipid-lowering strategies and hence a greater understanding of the mechanisms underlying its functional effects on SMC may provide alternative therapeutic targets.
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Riches
authors.forename: Larissa
authors.initials: L
authors.lastname: Franklin
authors.forename: Azhar
authors.initials: A
authors.lastname: Maqbool
authors.forename: Michelle
authors.initials: M
authors.lastname: Peckham
authors.forename: Matthew
authors.initials: M
authors.lastname: Adams
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Bond
authors.forename: Philip
authors.initials: P
authors.lastname: Warburton
authors.forename: Nicole T
authors.initials: NT
authors.lastname: Feric
authors.forename: Marlys L
authors.initials: ML
authors.lastname: Koschinsky
authors.forename: David J
authors.initials: DJ
authors.lastname: O'Regan
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ball
authors.forename: Neil A
authors.initials: NA
authors.lastname: Turner
authors.forename: Karen E
authors.initials: KE
authors.lastname: Porter
mesh_terms: D053241:Apoprotein(a) / Q000494:pharmacology*; D048430:Cell Shape / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D039302:Integrin alphaVbeta3; D016212:Transforming Growth Factor beta; D011505:Protein-Tyrosine Kinases; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D053241:Apoprotein(a); D020742:rhoA GTP-Binding Protein
keywords: Ao; DMEM; Dulbecco's modified eagle medium; ERK; FCS; GAPDH; HP; Lipoprotein(a); Lp(a); MAPK; Migration; NFκB; PDGF; ROCK; Remodelling; Rho kinase; RhoA; SMC; SV; TGFβ; Vascular smooth muscle cells; alpha smooth muscle actin; aortic; apo(a); apolipoprotein(a); extracellular signal-regulated kinase; foetal calf serum; glyceraldehyde 3-phosphate dehydrogenase; high power; lipoprotein(a); mitogen activated protein kinase; nuclear factor kappa B; platelet-derived growth factor-BB; saphenous vein; smooth muscle cell; transforming growth factor beta; α-SMA