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

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. 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. Studies have shown that elevated concentrations of plasma lipoprotein(a) (Lp(a)) 2The abbreviations used are: Lp(a), lipoprotein(a); apo(a), apolipoprotein(a); r-apo(a), recombinant apo(a); K, kringle; HUVEC, human umbilical vein endothelial cells; r-apo(a), recombinant apo(a); LBS, lysine-binding site; TNFα, tumor necrosis factor-α; ϵ-ACA, ϵ-aminocaproic acid; MLC, myosin light chain; MLCK, MLC kinase; MLCP, MLC phosphatase; RhoK, Rho kinase; LDL, low density lipoprotein; EC, endothelial cell; PBS, phosphate-buffered saline; TRITC, tetramethylrhodamine isothiocyanate. (>30 mg/dl or >100 nm) are a risk factor for a variety of vascular diseases, including coronary heart disease, ischemic stroke, and venous thrombosis (1Koschinsky M.L. Cardiovasc. Hematol. Disord. Drug Targets. 2006; 6: 267-278Crossref PubMed Scopus (36) Google Scholar, 2Anuurad E. Boffa M.B. Koschinsky M.L. Berglund L. Clin. Lab. Med. 2006; 26: 751-772Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Lp(a) is identical to low density lipoprotein (LDL) in both lipid composition as well as the presence of apolipoproteinB-100. However, Lp(a) is clearly distinguishable from LDL by the presence of the unique glycoprotein apolipoprotein(a) (apo(a)) that is disulfide-linked to apolipoproteinB-100 in LDL by a single disulfide bond (3Koschinsky M.L. Côté G.P. Gabel B. van der Hoek Y.Y. J. Biol. Chem. 1993; 268: 19819-19825Abstract Full Text PDF PubMed Google Scholar). Apo(a) bears a striking homology with plasminogen and contains multiple repeats of a sequence that resembles plasminogen kringle IV as well as sequences homologous to the kringle V and protease regions of plasminogen (4McLean J.W. Tomlinson J.E. Kuang W. Eaton D.L. Chen E. Fless G. Scanu A. Lawn R.M. Nature. 1987; 330: 132-137Crossref PubMed Scopus (1597) Google Scholar). The protease domain in apo(a) cannot be activated by activators of plasminogen; therefore, it cannot develop protease activity and hence lacks fibrinolytic activity (5Gabel B.R. Koschinsky M.L. Biochemistry. 1995; 34: 15777-15784Crossref PubMed Scopus (50) Google Scholar). The kingle IV-like domain in apo(a) is classified into 10 types (KIV1–10); the KIV2 sequence is present in a variable number of identically repeated copies (from 3 to >40) giving rise to Lp(a) isoform size heterogeneity (6van der Hoek Y.Y. Wittekoek M.E. Beisiegel U. Kastelein J.J.P. Koschinsky M.L. Hum. Mol. Genet. 1993; 2: 361-366Crossref PubMed Scopus (174) Google Scholar, 7Lackner D. Cohen J.C. Hobbs H.H. Hum. Mol. Genet. 1993; 2: 933-940Crossref PubMed Scopus (315) Google Scholar). Kringle IV types 5–8 (KIV5–8) possess “weak” lysine-binding sites (LBS) (8Becker L. McLeod R.S. Marcovina S.M. Yao Z. Koschinsky M.L. J. Biol. Chem. 2001; 276: 36155-36162Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar) that mediate the non-covalent interactions between apo(a) and apolipoproteinB-100, which precede disulfide bond formation to form Lp(a). Another weak lysine-binding site is evident in kringle V (KV), and, as yet, its function is not known. Apo(a) also contains a “strong” LBS within kringle IV type 10 (KIV10), which is thought to mediate binding of apo(a) and Lp(a) to other physiological ligands such as fibrin and extracellular matrix proteins (9Sangrar W. Koschinsky M.L. Biochem. Cell Biol. 2000; 78: 519-525Crossref PubMed Scopus (14) Google Scholar, 10Hughes S.D. Lou X.J. Ighani S. Verstuyft J. Grainger D.J. Lawn R.M. Rubin E.M. J. Clin. Invest. 1997; 100: 1493-1500Crossref PubMed Scopus (54) Google Scholar). Although many potential mechanisms by which Lp(a) might promote atherogenesis have been proposed (1Koschinsky M.L. Cardiovasc. Hematol. Disord. Drug Targets. 2006; 6: 267-278Crossref PubMed Scopus (36) Google Scholar, 2Anuurad E. Boffa M.B. Koschinsky M.L. Berglund L. Clin. Lab. Med. 2006; 26: 751-772Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar), the relevant mechanism(s) have yet to be definitively established. This uncertainty is likely a function of the complex, modular structure of apo(a). The vascular endothelium forms a selective permeable barrier between the blood and the interstitial space of all organs and participates in the regulation of macromolecule transport and blood cell trafficking through the vessel wall. Failure of endothelial barrier function can occur when endothelial cells are exposed to inflammatory mediators, a key event in the initial stages of atherosclerosis. Loss of barrier function results from the opening of gaps between adjacent cells as a consequence of both a loss of cell adhesion and activation of the endothelial contractile machinery (11Michel C.C. Curry F.E. Physiol. Rev. 1999; 79: 703-761Crossref PubMed Scopus (738) Google Scholar). Generation of contractile forces by endothelial cells (ECs) can cause adjacent cells to retract from each other (12Schnittler H.J. Wilke A. Gress T. Suttorp N. Drenckhahn D. J. Physiol. 1990; 431: 379-401Crossref PubMed Scopus (183) Google Scholar, 13Goeckeler Z.M. Wysolmerski R.B. J. Cell Biol. 1995; 130: 613-627Crossref PubMed Scopus (379) Google Scholar). The importance of this actin-myosin-based contractile apparatus for dynamic adaptation of endothelial barrier function under physiological conditions as well as for the development of barrier failure has been well established (13Goeckeler Z.M. Wysolmerski R.B. J. Cell Biol. 1995; 130: 613-627Crossref PubMed Scopus (379) Google Scholar, 14Bodmer J.E. Van Engelenhoven J. Reyes G. Blackwell K. Kamath A. Shasby D.M. Moy A.B. Microvasc. Res. 1997; 53: 261-271Crossref PubMed Scopus (13) Google Scholar, 15Gündüz D. Hirche F. Härtel F.V. Rodewald C.W. Schäfer M. Pfitzer G. Piper H.M. Noll T. Cardiovasc. Res. 2003; 59: 470-478Crossref PubMed Scopus (35) Google Scholar). Various physiological agents such as tumor necrosis factor-α (TNFα), thrombin, oxidized LDL, and Lp(a) have been demonstrated to elicit some manifestations of endothelial barrier dysfunction (16Wojciak-Stothard B. Entwistle A. Garg R. Ridley A.J. J. Cell. Physiol. PubMed Scopus Google Scholar, A.B. J. Physiol. Google Scholar, M. M. M. J.W. M. W. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M. E. J.C. T. K. Marcovina S.M. Boffa M.B. Côté G.P. Koschinsky M.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). agents the endothelial by cell through of the cytoskeleton to increase the size of gaps and the of inflammatory cells and key event in the regulation of endothelial barrier function is is by phosphorylation of the myosin light chain which is with (13Goeckeler Z.M. Wysolmerski R.B. J. Cell Biol. 1995; 130: 613-627Crossref PubMed Scopus (379) Google Scholar, J. Cell. Physiol. 1995; PubMed Scopus Google Scholar). such as and in MLC phosphorylation, stress fiber formation, and increased endothelial via Rho/Rho kinase-dependent mechanisms G.P. R. van Res. PubMed Google Scholar). has been proposed to mediate the of MLC phosphatase via phosphorylation of its leading to a of MLC phosphorylation in to J. Physiol. 2000; PubMed Scopus Google Scholar, K. M. M. K. M. B. J. T. K. A. K. PubMed Scopus Google Scholar). The activity of Rho in to to be mediated by through its to the of MLCP, thus this phosphatase M. M. H.J. K. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We previously have demonstrated that Lp(a), through its apo(a) elicits rearrangement of the actin cytoskeleton in human umbilical vein endothelial cells and human coronary endothelial cells, characterized by increased stress fiber formation, of vascular endothelial and increased cell M. E. J.C. T. K. Marcovina S.M. Boffa M.B. Côté G.P. Koschinsky M.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), treatment with LDL or plasminogen effects were mediated by increased MLC phosphorylation via a signaling the mechanisms in apo(a)-induced in endothelial cell and is not known. In the present we the that apo(a)-induced stress fiber formation and increased is by phosphorylation of we a of recombinant apo(a) variants in which domains were or to the sequences in apo(a) that mediate endothelial barrier dysfunction. We demonstrate a key role for the strong LBS in KIV10 of apo(a) in a signaling pathway to MLC phosphorylation via of MLCP, which and permeability. Taken together, these results a by which the apo(a) component of Lp(a) can promote endothelial barrier dysfunction atherogenesis. and of of the recombinant apo(a) variants with the of apo(a) were and in human cells as previously M.L. Tomlinson J.E. K. Eaton D.L. Lawn R.M. Biochemistry. PubMed Scopus Google Scholar, W. Gabel B.R. Boffa M.B. Marcovina S.M. M.E. Koschinsky M.L. Biochemistry. 1997; PubMed Scopus Google Scholar). the using the W. Gabel B.R. Boffa M.B. Marcovina S.M. M.E. Koschinsky M.L. Biochemistry. 1997; PubMed Scopus Google Scholar). Apo(a) is as previously with some L. Koschinsky M.L. Biochemistry. PubMed Scopus Google Scholar). the recombinant protein a of a The with and proteins were by the of and the and the using of the variants is in with a that all of the variants are of the molecular cells were on a density of in and to treatment with apo(a) cells were with and for in This with apo(a) and the cells were for this the cells were for as were with in for with PBS, and with in for and with for cells were with tetramethylrhodamine in 10 of and cells were with in for with PBS, cells were for with and in in the with PBS, were to using an and using a with a were using a and were a of with and into of the were for with of the The of of the cells the treatment by and of the cells in of the the cells were in the well with in a of some also apo(a) variants or a The in the well with of of from the well and with of The with of PBS, and with a using an of and of MLC phosphorylation by followed by were to in and with apo(a) variants for The were by of of were into and for were and were with to were in and were to on a and proteins were to in were with in in and for MLC with or for MLC with MLC for were with and with of the in for were with were with and exposed to were using a and the density of the using The of MLC to the MLC in the MLC were to in a were in a using a followed by as in the were by using or were with were using or for or of the using The of MYPT1 to the MYPT1 in the Rho activation as in the were to in and with or for were with this and the cell were into on with the were with for were and The were with and were in using followed by as in the were by using and for the or for the were with were using Apo(a) in studies have demonstrated that apo(a) and Lp(a) stress fiber which domain or domains in apo(a) these we have and a of variants and of key domains in the contains all of the domains in apo(a) and in a relevant isoform with copies of KIV2 domains J. Physiol. 2000; PubMed Scopus Google Scholar). contains an acid that the strong LBS in a of KV domain a actin stress and as the of the cells stress were the cell and were in the regions of the The of concentrations to nm) observed of and of not a of used for with in an increased number of stress the cells and, a with evident formation an Lp(a) isoform a form of apo(a), a of to a of which is as the risk for Lp(a) the effects of apo(a) observed occur relevant We the of each of our to stress fiber formation and We variants the and C-terminal domains of increased both stress fiber formation and a role of C-terminal of this and In to and other variants and C-terminal sequences stress fiber formation leading to endothelial formation and KIV10 the kringle that in all and the in which the strong LBS in KIV10 on stress fiber formation and which lacks KV and its weak LBS, similar effects on stress fiber formation and to and by Apo(a) to in and by a Rho and that the increase in stress fiber formation and loss of via of an to permeability. with this treatment of with in an increase in of that and this for and plasminogen were used as and (16Wojciak-Stothard B. Entwistle A. Garg R. Ridley A.J. J. Cell. Physiol. PubMed Scopus Google Scholar, M. E. J.C. T. K. Marcovina S.M. Boffa M.B. Côté G.P. Koschinsky M.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In with the results for stress fiber formation and all the that contain KIV10 and in a increase in of treatment and with its of effects on stress fiber formation and not increase permeability. in a increase in In with the on the strong LBS in KIV10 for the effects of apo(a), of ϵ-ACA, a lysine abolished as the of a inhibitor findings indicate that apo(a) via a pathway dependent on cell and signaling through of MLC by and by a Rho and of MLC is for myosin activation and stress fiber formation, leading to an increase in and (13Goeckeler Z.M. Wysolmerski R.B. J. Cell Biol. 1995; 130: 613-627Crossref PubMed Scopus (379) Google Scholar). We have previously shown that treatment with apo(a) in increase in MLC phosphorylation in a M. E. J.C. T. K. Marcovina S.M. Boffa M.B. Côté G.P. Koschinsky M.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In which the in apo(a) mediate an increase in MLC phosphorylation, were exposed to and the of MLC phosphorylation by can be in treatment with MLC phosphorylation between and of concentrations MLC phosphorylation not and plasminogen nm) were used as and of the of MLC phosphorylation decreased a that the observed in the In with the and both and a increase in MLC phosphorylation, and not and treatment in MLC phosphorylation which to a similar to that of cells, not in increased MLC phosphorylation 10 of which it a to that by and not MLC phosphorylation, a critical role for the strong LBS in KIV10 in MLC phosphorylation and with a increase in a increase in MLC phosphorylation that that by apo(a) that lacks the weak LBS in KV domain the on MLC phosphorylation as not with the increase by this a role for the weak LBS in KV in the MLC phosphorylation by apo(a). with completely increase in MLC phosphorylation in a the other MLC phosphorylation not all by treatment not of by abolished the of MLC phosphorylation of also completely and in MLC phosphorylation not and N. M. T. M. F. M. K. J. Cell Biol. 1999; PubMed Scopus Google Scholar) have that activation MLC phosphorylation by potential phosphorylation of MLC and via phosphorylation of the of myosin phosphatase the phosphorylation of MLC by that and not is for the MLC phosphorylation by apo(a) by a and myosin phosphatase via phosphorylation of its N. M. T. M. F. M. K. J. Cell Biol. 1999; PubMed Scopus Google as to MLC we apo(a) the of MYPT1 phosphorylation in with in a increase in MYPT1 phosphorylation in a with the of MYPT1 phosphorylation decreased to or with effects on and MLC phosphorylation, and also phosphorylation in a similar to and and to on MYPT1 phosphorylation of completely abolished MYPT1 phosphorylation as as well as that mediated by and not The of completely abolished MYPT1 phosphorylation in with the importance of the strong LBS in this as by the results with and shown that apo(a), in a dependent on the strong LBS in through phosphorylation of we apo(a) is to were with or and cell were for the of the of In with the not the the formation of with the of observed between and 10 of apo(a) treatment that apo(a), through its strong LBS in cytoskeleton rearrangement and a increase in through a pathway. plasma concentrations of Lp(a) have been as a risk factor for the development of a variety of including coronary heart (1Koschinsky M.L. Cardiovasc. Hematol. Disord. Drug Targets. 2006; 6: 267-278Crossref PubMed Scopus (36) Google Scholar, 2Anuurad E. Boffa M.B. Koschinsky M.L. Berglund L. Clin. Lab. Med. 2006; 26: 751-772Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). evidence has to that Lp(a) is a (1Koschinsky M.L. Cardiovasc. Hematol. Disord. Drug Targets. 2006; 6: 267-278Crossref PubMed Scopus (36) Google Scholar, 2Anuurad E. Boffa M.B. Koschinsky M.L. Berglund L. Clin. Lab. Med. 2006; 26: 751-772Abstract Full Text Full Text PDF PubMed Scopus (86) Google the mechanisms by which it its effects plasma Lp(a) are to lipid or S.M. Koschinsky M.L. S. Clin. Chem. 2003; PubMed Scopus Google Scholar, B. 1997; PubMed Scopus (54) Google Scholar), it is critical to the mechanisms of Lp(a) as be potential for to which of the of Lp(a) are in is to domains of apo(a) mediate the it has been demonstrated that an apo(a) the strong LBS in KIV10 are to apo(a) Lou X.J. K. Rubin E.M. Lawn R.M. J. Clin. Invest. 1997; 100: PubMed Scopus Google Scholar). We in the that this LBS is to mediate the effects of apo(a) on actin in that in endothelial a critical event in the Lp(a) has been shown to a variety of endothelial cell Lp(a) has been shown to cell by the of a number of adhesion on endothelial cells such as vascular cell adhesion adhesion and S. S. S. Koschinsky M.L. M. J. PubMed Scopus Google Scholar, S. S. S. M. K. N. T. PubMed Scopus Google Scholar, Res. 2000; 100: Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Apo(a) also the of the a in endothelial cells D.L. J. M. Gabel B.R. M.B. Koschinsky M.L. 2000; PubMed Scopus Google Scholar). Lp(a) concentrations in plasma also to endothelial dysfunction in studies have demonstrated in with Lp(a) D. G. D.J. J.E. J. Clin. Invest. PubMed Scopus Google Scholar). in Lp(a) has been with of endothelial in K. T. S. J. 1995; 26: PubMed Scopus Google Scholar, M. J. A. 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Taken together, endothelial barrier dysfunction is mediated by activation of myosin via pathway that This results in an increase in MLC phosphorylation and stress fiber formation and thus an increase in permeability. In the present we have established a that the strong LBS in apo(a) kringle IV type 10 is for in We that all variants and stress fiber formation, MLC phosphorylation, MYPT1 phosphorylation, and variants KIV10 or its strong LBS and and plasminogen on of these of completely abolished all of that the role of lysine-binding sites within apo(a) is In to the strong LBS in apo(a) contains LBS in and on the of variants that these domains and of these weak LBS to a role in the effects of apo(a) on endothelial cells, these variants with to some We have previously shown that the is to plasminogen plasminogen activation in the of fibrin Boffa M.B. Marcovina S.M. M.E. Koschinsky M.L. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the KV domain the of the apo(a) Lp(a) not to the presence of a strong LBS in KIV10 and apo(a) lacks KV J. Boffa M.B. Z. Koschinsky M.L. Biochemistry. PubMed Scopus Google Scholar). In the it that it is the weak LBS in KV that for the of this kringle to the effects of apo(a), treatment with a a in the KV weak LBS similar effects on MLC phosphorylation and as treatment with not it is the strong LBS in KIV10 that is for the effects of apo(a) on the is that apo(a) in a with an as yet in endothelial cells to signaling the to effects of apo(a) on the it is that in are The is that apo(a) to of the plasminogen to plasminogen and are by both protein the component of the and cell A. Clin. 1995; Full Text PDF PubMed Scopus Google Scholar, M. D.M. PubMed Scopus Google Scholar). the protein has been to Rho activation or the actin cytoskeleton A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). are of lipid which can to and Rho PubMed Scopus Google Scholar, H.H. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of these were to be critical for the effects of apo(a) in our M. E. J.C. T. K. Marcovina S.M. Boffa M.B. Côté G.P. Koschinsky M.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, we have shown that plasminogen has on actin cytoskeleton signaling to the actin or cell M. E. J.C. T. K. Marcovina S.M. Boffa M.B. Côté G.P. Koschinsky M.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and it is that apo(a) with a plasminogen in a plasminogen to mediate these or apo(a) through a In we have characterized the leading to barrier dysfunction by apo(a) in a dependent on the strong LBS in KIV10. is as apo(a), through its in to an which to increased MLC phosphorylation, stress fiber formation, and in a pathway and the activity of is not apo(a) a of which is the likely cause of the increased endothelial by apo(a). The be by of the actin In addition, apo(a) promote the of through of signaling In this our that mediates the of and from into the not of KIV10 as the domain in apo(a) that mediates in endothelial cells a for the stages of atherosclerosis.

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