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      Apolipoprotein(a) acts as a chemorepellent to human vascular smooth muscle cells via integrin α Vβ 3 and RhoA/ROCK-mediated mechanisms ☆

      research-article
      Author(s): a , b , a , a , b , c , d , d , a , e , e , b , f , a , b , a , b , a , b , *
      Publication date PMC-release:
      Journal: The International Journal of Biochemistry & Cell Biology
      Publisher: Elsevier
      Keywords: Ao, aortic, α-SMA, alpha smooth muscle actin, apo(a), apolipoprotein(a), DMEM, Dulbecco's modified eagle medium, ERK, extracellular signal-regulated kinase, FCS, foetal calf serum, GAPDH, glyceraldehyde 3-phosphate dehydrogenase, HP, high power, Lp(a), lipoprotein(a), MAPK, mitogen activated protein kinase, NFκB, nuclear factor kappa B, PDGF, platelet-derived growth factor-BB, ROCK, Rho kinase, SV, saphenous vein, SMC, smooth muscle cell, TGFβ, transforming growth factor beta, Lipoprotein(a), Vascular smooth muscle cells, Migration, RhoA, Remodelling

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          Highlights

          • •

            Acute application of apo(a) to smooth muscle cells induced chemorepulsion.

          • •

            Chronic application (>24 h) induced stress fibre formation and cell spreading.

          • •

            Effects of apo(a) were mediated by integrin α Vβ 3, tyrosine kinases and RhoA/ROCK.

          • •

            Apo(a) impaired SMC motility which potentially contributes to vascular dysfunction.

          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 α Vβ 3-dependent, but transforming growth factor β-independent. SMC manipulation through RhoA gene silencing, Rho kinase inhibition, statin pre-treatment, α Vβ 3 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.

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          Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes.

          Sotirios Tsimikas, Claes Bergmark, Reinaldo Beyer … (2003)
          This study was conducted to test the hypothesis that plasma markers of oxidized low-density lipoprotein (OxLDL) reflect acute coronary syndromes (ACS). Oxidized LDL contributes to the pathogenesis of atherosclerosis, but its role in ACS is not established. Serial plasma samples were prospectively obtained from patients with an acute myocardial infarction (MI) (n = 8), unstable angina (UA) (n = 15), stable coronary artery disease (CAD) (n = 17), angiographically normal coronary arteries (n = 8), and from healthy subjects (n = 18), at entry into the study, hospital discharge (MI group only), and at 30, 120, and 210 days. Chemiluminescent enzyme-linked immunosorbent assay was used to quantitate plasma levels of: 1) immunoglobulin (Ig)M and IgG OxLDL autoantibody titers (presented as a mean OxLDL autoantibody titer by averaging the results of four distinct epitopes); 2) LDL-autoantibody immune complexes (LDL-IC); and 3) minimally OxLDL measured by antibody E06 (OxLDL-E06), as determined by the content of oxidized phospholipids (OxPL) per apolipoprotein B-100. Baseline OxLDL IgG autoantibody levels were higher in the MI group (p < 0.0001). At 30-day follow-up, the mean IgM OxLDL titers increased by 48% (p < 0.001) and 20% (p < 0.001), and IgM LDL-IC increased by 60% (p < 0.01) and 26% (p < 0.01) in the MI and UA groups, respectively. The OxLDL-E06 levels increased by 54% (p < 0.01) in the MI group at hospital discharge and by 36% at 30 days. No significant changes in any OxLDL markers were noted in the other groups. The OxLDL-E06 levels strongly paralleled the acute rise in lipoprotein(a), or Lp(a), in the MI group, suggesting that toxic OxPL are preferentially bound to Lp(a). Oxidized LDL-E06 also correlated extremely well with Lp(a) in the entire cohort of patients (r = 0.91, p < 0.0001). Circulating OxLDL-specific markers strongly reflect the presence of ACS, implying immune awareness to newly exposed oxidation-specific epitopes and possible release of OxLDL in the circulation. The OxLDL-E06 measurements provide novel insights into plaque rupture and the potential atherogenicity of Lp(a).
          Article 0 comments Cited 62 times – based on 0 reviews     Review now
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            Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies.

            Sotirios Tsimikas, Jennifer L Hall (2012)
            Recent published studies have provided increasing evidence that lipoprotein(a) [Lp(a)] may be a potential causal, genetic, independent risk factor for cardiovascular disease (CVD). Lp(a) levels >25 mg/dl are present in ∼30% of Caucasians and 60% to 70% of Blacks. Lp(a) is composed of apolipoprotein B-100 and apolipoprotein (a) [(apo(a)]. Circulating Lp(a) levels are primarily influenced by the LPA gene without significant dietary or environmental effects, mediating CVD risk throughout the patient's lifetime. Recent clinical outcomes studies, meta-analyses, and Mendelian randomization studies, in which randomization of Lp(a) levels is achieved through the random assortment of LPA gene variants thereby removing confounders, have shown that genetically determined Lp(a) levels are continuously and linearly related to risk of CVD. Currently, Lp(a) pathophysiology is not fully understood, and specifically targeted therapies to lower Lp(a) are not available. We provide a rationale for increased basic and clinical investigational efforts to further understand Lp(a) pathophysiology and assess whether reducing Lp(a) levels minimizes CVD risk. First, a detailed understanding of Lp(a) synthesis and clearance has not been realized. Second, several mechanisms of atherogenicity are known to varying extent, but the relative contributions of each are not known. Lp(a) may be atherothrombotic through its low-density lipoprotein moiety, but also through apo(a), including its ability to be retained in the vessel wall and mediate pro-inflammatory and proapoptotic effects including those potentiated by its content of oxidized phospholipids, and antifibrinolytic effects. Finally, development of specific Lp(a)-lowering agents to potently lower Lp(a) will allow testing of mechanistic hypotheses in animal models and the design of randomized clinical trials to assess reduction in CVD. A convergence of academic, scientific, pharmaceutical, and National Institutes of Health priorities and efforts can make this a reality in the next decade. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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              Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein.

              Sotirios Tsimikas, Bradley H Strauss, Allan K H Lau … (2004)
              This study was performed to assess whether oxidized low-density lipoprotein (OxLDL) levels are elevated after percutaneous coronary intervention (PCI). Patients (n=141) with stable angina pectoris undergoing PCI had serial venous blood samples drawn before PCI, after PCI, and at 6 and 24 hours, 3 days, 1 week, and 1, 3, and 6 months. Plasma levels of OxLDL-E06, a measure of oxidized phospholipid (OxPL) content on apolipoprotein B-100 detected by antibody E06, lipoprotein(a) [Lp(a)], autoantibodies to malondialdehyde (MDA)-LDL and copper-oxidized LDL (Cu-OxLDL), and apolipoprotein B-100-immune complexes (apoB-IC) were measured. OxLDL-E06 and Lp(a) levels significantly increased immediately after PCI by 36% (P<0.0001) and 64% (P<0.0001), respectively, and returned to baseline by 6 hours. In vitro immunoprecipitation of Lp(a) from selected plasma samples showed that almost all of the OxPL detected by E06 was bound to Lp(a) at all time points, except in the post-PCI sample, suggesting independent release and subsequent reassociation of OxPL with Lp(a) by 6 hours. Strong correlations were noted between OxLDL-E06 and Lp(a) (r=0.68, P<0.0001). MDA-LDL and Cu-OxLDL autoantibodies decreased, whereas apoB-IC levels increased after PCI, but both returned to baseline by 6 hours. Subsequently, IgM autoantibodies increased and peaked at 1 month and then returned to baseline, whereas IgG autoantibodies increased steadily over 6 months. PCI results in acute plasma increases of Lp(a) and OxPL and results in short-term and long-term immunologic responses to OxLDL. OxPL that are released or generated during PCI are transferred to Lp(a), suggesting that Lp(a) may contribute acutely to a protective innate immune response. In settings of enhanced oxidative stress and chronically elevated Lp(a) levels, the atherogenicity of Lp(a) may stem from its capacity as a carrier of proinflammatory oxidation byproducts.
              Article 0 comments Cited 48 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Karen E. Porter
                Journal
                Journal ID (nlm-ta): Int J Biochem Cell Biol
                Journal ID (iso-abbrev): Int. J. Biochem. Cell Biol
                Title: The International Journal of Biochemistry & Cell Biology
                Publisher: Elsevier
                ISSN (Print): 1357-2725
                ISSN (Electronic): 1878-5875
                Publication date PMC-release: 1 August 2013
                Publication date (Print): August 2013
                Volume: 45
                Issue: 8
                Pages: 1776-1783
                Affiliations
                [0005]Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK
                [0010]Multidisciplinary Cardiovascular Research Centre (MCRC), University of Leeds, Leeds, UK
                [0015]Institute of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
                [0020]Bioscreening Technology Group, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
                [0025]Department of Biochemistry, University of Windsor, Ontario, Canada
                [0030]Department of Cardiac Surgery, The Yorkshire Heart Centre, Leeds General Infirmary, Leeds, UK
                Author notes
                [* ]Corresponding author at: Division of Cardiovascular and Diabetes Research, Worsley Building, Clarendon Way, University of Leeds, Leeds LS2 9JT, UK. Tel.: +44 0113 3434806; fax: +44 0113 3434803. medkep@ 123456leeds.ac.uk k.e.porter@ 123456Leeds.ac.uk
                Article
                Publisher ID: BC4043
                DOI: 10.1016/j.biocel.2013.05.021
                PMC ID: 3731554
                PubMed ID: 23726972
                SO-VID: 2b40b6b7-f289-4bcf-8127-4ac52779fa75
                Copyright © © 2013 The Authors
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 3 January 2013
                Date revision received : 24 April 2013
                Date accepted : 21 May 2013
                Categories
                Subject: Article

                ScienceOpen disciplines: Biochemistry
                Keywords: ao, aortic,α-sma, alpha smooth muscle actin,apo(a), apolipoprotein(a),dmem, dulbecco's modified eagle medium,erk, extracellular signal-regulated kinase,fcs, foetal calf serum,gapdh, glyceraldehyde 3-phosphate dehydrogenase,hp, high power,lp(a), lipoprotein(a),mapk, mitogen activated protein kinase,nfκb, nuclear factor kappa b,pdgf, platelet-derived growth factor-bb,rock, rho kinase,sv, saphenous vein,smc, smooth muscle cell,tgfβ, transforming growth factor beta,lipoprotein(a),vascular smooth muscle cells,migration,rhoa,remodelling
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: ao, aortic, α-sma, alpha smooth muscle actin, apo(a), apolipoprotein(a), dmem, dulbecco's modified eagle medium, erk, extracellular signal-regulated kinase, fcs, foetal calf serum, gapdh, glyceraldehyde 3-phosphate dehydrogenase, hp, high power, lp(a), lipoprotein(a), mapk, mitogen activated protein kinase, nfκb, nuclear factor kappa b, pdgf, platelet-derived growth factor-bb, rock, rho kinase, sv, saphenous vein, smc, smooth muscle cell, tgfβ, transforming growth factor beta, lipoprotein(a), vascular smooth muscle cells, migration, rhoa, remodelling

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