Key points are not available for this paper at this time.
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. 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. The vascular endothelium acts as a pivotal regulator in vessel wall homeostasis by forming a selective barrier between components of the blood and extravascular tissues. Increasing evidence suggests that atypical endothelial function is a key event in the initial stages of atherosclerosis development. More specifically, enhanced endothelial cell permeability and the expression of a procoagulant, antifibrinolytic, and proinflammatory phenotype by the endothelium is thought to be a crucial event in the onset of this disease (1Poredos P. Clin. Appl. Thromb. Hemost. 2001; 7: 276-280Crossref PubMed Scopus (54) Google Scholar). Various physiological agents have been identified that elicit some manifestations of endothelial dysfunction. These include growth factors, inflammatory cytokines such as tumor necrosis factor-α (2Wojciak-Stothard B. Entwistle A. Garg R. Ridley A.J. J. Cell. Physiol. 1998; 176: 150-165Crossref PubMed Scopus (348) Google Scholar), vasoactive substances such as thrombin (3Lum H. Ashner J.L. Phillips P.G. Fletcher P.W. Malik A.B. Am. J. Physiol. 1992; 263: L219-L225PubMed Google Scholar), and mildly oxidized, but not native, low density lipoprotein (LDL) 1The abbreviations used are: LDL, low density lipoprotein; MLC, myosin light chain; Lp(a), lipoprotein(a); apo(a), apolipoprotein(a); HUVEC, human umbilical vein endothelial cell; HCAEC, human coronary artery endothelial cell; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis (acetoxymethyl ester); PBS, phospate-buffered saline; TRITC, tetramethylrhodamine isothiocyanate; PIPES, 1,4-piperazinediethanesulfonic acid; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling. 1The abbreviations used are: LDL, low density lipoprotein; MLC, myosin light chain; Lp(a), lipoprotein(a); apo(a), apolipoprotein(a); HUVEC, human umbilical vein endothelial cell; HCAEC, human coronary artery endothelial cell; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis (acetoxymethyl ester); PBS, phospate-buffered saline; TRITC, tetramethylrhodamine isothiocyanate; PIPES, 1,4-piperazinediethanesulfonic acid; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling. (4Essler M. Retzer M. Bauer M. Heemsker J.W. Aepfelbacher M. Seiss W. J. Biol. Chem. 1999; 274: 30361-30364Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Many of these agents alter the permeability of the endothelium by stimulating cell contraction, thereby increasing the size of intercellular gaps and facilitating entry of inflammatory cells and atherogenic lipoproteins. The mechanism by which these agents are able to alter properties of the endothelium has received much attention. Endothelial cell contraction is mediated by interactions between actin filaments and non-muscle myosin II. The activity of non-muscle myosin II is largely regulated by phosphorylation of its regulatory myosin light chain (MLC) at Ser-19 (5Garcia J.G. Davis H.W. Patterson C.E. J. Cell. Physiol. 1995; 163: 510-522Crossref PubMed Scopus (482) Google Scholar). MLC phosphorylation activates myosin thus enabling it to associate with filamentous actin (F-actin), resulting in the assembly of stress fibers, the formation of mature focal adhesions, and cell contraction (6Goeckler Z.M. Wysolmerski R.B. J. Cell Biol. 1995; 130: 613-627Crossref PubMed Scopus (376) Google Scholar, 7Chrzanowska-Wodnicka M. Burridge K. J. Cell Biol. 1996; 133: 1403-1415Crossref PubMed Scopus (1384) Google Scholar). The MLC phosphorylation state is a function of the balance between MLC kinases (principally the Ca2+-calmodulin-dependent myosin light chain kinase) and phosphatases (principally type 1 myosin-associated protein phosphatase) (8Verin A.D. Patterson C.E. Day M.A. Garcia J.G. Am. J. Physiol. 1995; 269: L99-L108PubMed Google Scholar, 9Somlyo A.P. Somlyo A.V. Nature. 1994; 372: 231-236Crossref PubMed Scopus (1715) Google Scholar). Rho kinase, an effector of the small GTPase Rho, has both direct and indirect effects on MLC phosphorylation (10Amano M. Ito M. Kimura K. Fukata Y. Chihara K. Nakano T. Matsuura M. Kaibuchi K. J. Biol. Chem. 1996; 271: 20246-20249Abstract Full Text Full Text PDF PubMed Scopus (1654) Google Scholar). Rho kinase has been found to directly phosphorylate the MLC at Ser-19 albeit at a much lower rate than MLC kinase. In addition, Rho kinase effectively enhances MLC phosphorylation through inactivation of myosin phosphatase (11Kimura K. Ito M. Amano M. Chihara K. Fukata Y. Nakafuku M. Yamamori B. Feng J. Nakano T. Okawa K. Iwamatsu A. Kaibuchi K. Science. 1996; 273: 245-248Crossref PubMed Scopus (2412) Google Scholar, 12Kawano Y. Fukata Y. Oshiro N. Amano M. Nakamura T. Ito M. Matsumura F. Inagaki M. Kaibuchi K. J. Cell Biol. 1999; 147: 1023-1038Crossref PubMed Scopus (469) Google Scholar). It has been demonstrated that the ability of tumor necrosis factor-α and mildly oxidized LDL to elicit stress fiber formation, increase MLC phosphorylation, and promote retraction in cultured endothelial cells is mediated by a Rho- and Rho kinase-dependent signaling pathway (2Wojciak-Stothard B. Entwistle A. Garg R. Ridley A.J. J. Cell. Physiol. 1998; 176: 150-165Crossref PubMed Scopus (348) Google Scholar, 4Essler M. Retzer M. Bauer M. Heemsker J.W. Aepfelbacher M. Seiss W. J. Biol. Chem. 1999; 274: 30361-30364Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). In addition to Rho, the GTP-binding proteins Rac and Cdc42 also play central roles in controlling cytoskeletal reorganization. While Rho is the predominant regulator of actin stress fiber formation (13Ridley A.J. Hall A. Cell. 1992; 70: 389-399Abstract Full Text PDF PubMed Scopus (3788) Google Scholar), Rac and Cdc42 are involved in lamellipodia and filopodia formation, respectively, and promote the assembly of small, peripheral adhesion complexes (14Bishop A.L. Hall A. Biochem. J. 2000; 348: 241-255Crossref PubMed Scopus (1655) Google Scholar). Members of the Rho family of GTPases have also been found to regulate intercellular junctions and thus permeability (2Wojciak-Stothard B. Entwistle A. Garg R. Ridley A.J. J. Cell. Physiol. 1998; 176: 150-165Crossref PubMed Scopus (348) Google Scholar, 15Nobes C.D. Hall A. Biochem. Soc. Trans. 1995; 23: 456-459Crossref PubMed Scopus (299) Google Scholar, 16Wojciak-Stothard B. Potempa S. Eichholtz T. Ridley A.J. J. Cell Sci. 2001; 114: 1343-1355Crossref PubMed Google Scholar). Both case-control and prospective studies have shown that lipoprotein(a) (Lp(a)) is a risk factor for coronary heart disease (17Marcovina S.M. Koschinsky M.L. Curr. 1999; PubMed Scopus Google Scholar, S.M. Koschinsky M.L. PubMed Scopus Google Scholar, Curr. PubMed Scopus Google Scholar). Lp(a) is similar to LDL in of and the of the Lp(a) is LDL by the of the apolipoprotein(a) (apo(a)) that is to by a Sci. S. A. PubMed Scopus Google Scholar, M.L. B. J. Biol. Chem. Full Text PDF PubMed Google Scholar). Apo(a) with the and of a that is similar to as as a of similar to the and of J.W. W. A. Nature. PubMed Scopus Google Scholar). Lp(a) has been as a risk factor for vascular the of the of Lp(a) in atherosclerosis roles for Lp(a) in and cell in and of as as of endothelial have been S.M. Koschinsky M.L. PubMed Scopus Google Scholar). the of Lp(a) on endothelial cell and barrier function has to be In the study, we have the of the apo(a) component of Lp(a) in cultured endothelial cell cytoskeleton reorganization. the Apo(a) stress fiber formation, vascular endothelial and focal adhesion molecule reorganization in a Rho- and Rho kinase-dependent manner. Rho and Rac but not Cdc42 are in actin stress fiber formation and VE-cadherin Apo(a) a time-dependent increase in MLC phosphorylation that is regulated by Rho and Rho kinase. Apo(a) not in increases in calcium levels, but its effects on cytoskeletal rearrangement are calcium-dependent. these results a mechanism by which Lp(a) promote endothelial cell of apo(a) and to a size M.L. K. PubMed Scopus Google was human cells with the expression as W. M.A. S.M. Koschinsky M.L. PubMed Scopus Google Scholar). was plasma as PubMed Scopus Google Scholar). Lp(a) was plasma by and as J. S. Biochem. 2001; PubMed Scopus Google Scholar). 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Cell umbilical vein endothelial cells and human coronary artery endothelial cells were and in endothelial growth which were and used at cells were at at a density of in and to with apo(a) and Lp(a), cells were for at in physiological 1 1 was with physiological apo(a), Lp(a), LDL, or and the cells were at for In some cells were with C3 transferase or C3 transferase, the was in the at a of for to the Y-27632, the cells were for as and were for with at a of in physiological saline; at this the was and apo(a) or Lp(a) was In cells were for and with or 1 to apo(a) were for as were with in for with PBS, and with for and with cells were with in PIPES, cells were with for at were with in for 1 at with PBS, cells were for 1 with and in VE-cadherin cells were as for were to an and a with a were a and were on as was an in cell to the a was for at to cells that were and were at a of with and of were for with of the the of apo(a) on endothelial in the was with apo(a) and 1 in a of The in the was with of cells were but in the of of the was and with of The was with of PBS, and was with a an of and of expression a a a and a were the of Hall expression the were on at The cells were with of the the of and of in a of of and 1 of in a of of were at for the were and for an The was to a of in of for at which cells were with and The cells were and as were with in and were for 1 with phosphorylation was by by were to in with and with apo(a) for In some cells were with C3 transferase or as to with The were by addition of of were and for at were and were with to were in and for were to on a and proteins were to in were with for at in and for MLC with 1 a or for MLC with MLC at were with and with of the in for at were with enhanced and to were a and the density of the was The of MLC was to the MLC in the of were on with at and for were with for at and in were in in a and at were to in the for was Apo(a) was at a of a 1 thrombin was at the of the calcium was a of and and an of calcium was as the of at to calcium and calcium Lp(a), through Apo(a) a in and a actin stress was the cell and was in the central of the with apo(a) caused a dramatic increase in the of stress the fiber formation was of and to between and Cell by increased formation between the as as apo(a) The effects of Lp(a) on were similar to that for The of stress was of In addition, stress fiber formation between and which the of stress to Lp(a) to be than apo(a) in actin stress fiber The risk for plasma concentrations of Lp(a) is to be or for an Lp(a) of the size in these plasma concentrations of Lp(a) of are in the S.M. H. J. 1996; Full Text PDF PubMed Google Scholar), we have stress fiber in by apo(a) concentrations as low as not the LDL of Lp(a) had an on stress fiber formation, were with LDL for LDL produced no in an that is with (4Essler M. Retzer M. Bauer M. Heemsker J.W. Aepfelbacher M. Seiss W. J. Biol. Chem. 1999; 274: 30361-30364Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). These that the on Lp(a) that the effects of this lipoprotein on actin cytoskeletal rearrangements is protein to was to the effects of apo(a) on the actin cytoskeleton were for the in of with for produced no increase in stress fiber formation results have Rho proteins in endothelial cell cell S. B. J. M. K. N. Am. J. Physiol. PubMed Scopus Google Scholar). In was used to the cytoskeletal apo(a) were by the of that no of not these results that the the for of to apo(a) caused in We that the increase in formation and of apo(a) to enhanced transendothelial permeability. with this with apo(a) a time-dependent increase in transendothelial of with These results that cytoskeletal by apo(a) are with increased to intercellular by Apo(a) to of VE-cadherin and by Rho and Rho stress fiber formation Rho and Rho kinase, were with C3 transferase and with C3 transferase or had or no on the of not but abolished the increase in stress fiber formation by apo(a) These results that of actin stress fiber formation by apo(a) through a Rho/Rho kinase-dependent results that apo(a) to increased cell and endothelial permeability. We that of contacts in in of the adhesion molecule is a protein that is to endothelial of is at of and as such acts as a for formation and increased vascular permeability M. F. B. J. Cell Biol. 1995; PubMed Scopus Google Scholar). cells VE-cadherin as the of the cells In with apo(a) had a VE-cadherin that with enhanced stress fiber formation and of VE-cadherin at of intercellular with formation between endothelial cells In addition, of Rho and its effector Rho kinase abolished the effects of apo(a) on VE-cadherin and Rho/Rho in by as for stress and play an in the actin cytoskeleton to the We the effects of apo(a) on the of focal in by the focal adhesion protein as a In were at the cell with apo(a) caused a dramatic of peripheral and an increase in focal the cell enhanced stress fiber formation to apo(a) with a redistribution of and formation of focal adhesions. with the key of the Rho/Rho kinase pathway in the of apo(a) and Lp(a) on stress fiber formation, the C3 transferase and the ability of apo(a) to elicit in the of focal and Lp(a) and Apo(a) in Endothelial the endothelial cells vascular Thromb. Biol. PubMed Scopus Google Scholar), we the ability of apo(a) and Lp(a) to cytoskeletal rearrangements in cultured endothelial cell type is to the effects of on the of with Lp(a) and apo(a) at for evoked the formation of actin stress in a similar to that in and with in the of in was Rho/Rho kinase-dependent In addition, a similar of apo(a) on the redistribution of focal was as by with as a not and VE-cadherin by Apo(a) by Rho and Rac but also to GTP-binding proteins may be involved in endothelial cytoskeletal reorganization and of by this were with of Rho Rac and Cdc42 with apo(a), and for in actin stress fiber and VE-cadherin of and did not alter the actin or VE-cadherin in cells are as and with and did not actin stress apo(a) addition and In addition, VE-cadherin was not in and cells with apo(a) and These that enhanced stress fiber formation and VE-cadherin reorganization caused by apo(a) on of both Rho and of with in a dramatic increase in the of stress did not VE-cadherin of apo(a) did not increase the of stress in but in a of VE-cadherin the effects of were with Cdc42 with stress fibers, than and filopodia VE-cadherin at the cell was not in cells with but of VE-cadherin were in the with apo(a) did not alter the of effects by and an increase in central stress was not and the cells and apo(a) did not to cause in VE-cadherin in the of MLC by Apo(a) and by Rho and Rho of the MLC is for myosin II and stress fiber formation and thus for cell contraction M. 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Cell Biol. 1996; 133: 1403-1415Crossref PubMed Scopus (1384) Google Scholar). a for apo(a) in MLC phosphorylation, were to apo(a), and the extent of MLC phosphorylation was by an for the of MLC phosphorylation than of apo(a) and the extent of MLC phosphorylation but at a than that in this is with the time-dependent effects of apo(a) on stress fiber formation with the results of the cells with the Rho inhibitor C3 transferase or the Rho kinase inhibitor abolished the ability of apo(a) to the extent of MLC phosphorylation Apo(a) in results in the roles for proteins in endothelial cytoskeletal rearrangement evoked by We to a pathway may be in to the effects of the were with the to in intracellular calcium with apo(a) did not evoke an increase in intracellular calcium These results that apo(a) is its effects through a Rho pathway than of myosin light chain kinase in a manner. this were with the to apo(a) of intracellular calcium by abolished the increase in stress produced by apo(a) the that apo(a) not intracellular calcium the effects of apo(a) are on calcium calcium is to of the MLC kinase that results in MLC phosphorylation and contraction A.D. Patterson C.E. Garcia J.G. Am. J. Cell Biol. 1998; PubMed Scopus Google Scholar, N. R. M. T. Am. J. Physiol. 2000; PubMed Google Scholar). this of endothelial MLC kinase, were with the MLC inhibitor by apo(a) an cytoskeletal that was with that in cells with VE-cadherin as were with and We conclude that the MLC kinase is for apo(a) to elicit its effects on the endothelial cytoskeleton and promote intercellular studies have demonstrated that Lp(a) is a risk factor for vascular the by which it its effects Lp(a) or its component apo(a) have been shown to endothelial cell function through a variety of studies have demonstrated in with Lp(a) J. Clin. 1994; PubMed Scopus Google Scholar). in Lp(a) has been with of endothelial in Y. H. K. T. S. J. Am. 1995; PubMed Scopus Google Scholar, M. J. A. J. Am. PubMed Scopus Google Scholar). 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We that the endothelial barrier function in with elevated Lp(a) explain a component of the enhanced risk for atherosclerotic in this We have also to the signaling cascade that is for the cytoskeleton by apo(a) The ability of to evoke these dramatic cytoskeletal rearrangements is mediated through a Rho/Rho kinase-dependent signaling pathway since of these intracellular the ability of apo(a) and Lp(a) to increase stress fiber formation and to promote in the of focal adhesions. of an effector of Rho in endothelial cells B. Potempa S. Eichholtz T. Ridley A.J. J. Cell Sci. 2001; 114: 1343-1355Crossref PubMed Google and cells (13Ridley A.J. Hall A. Cell. 1992; 70: 389-399Abstract Full Text PDF PubMed Scopus (3788) Google Scholar), also abolished these effects of In apo(a) its effects on the endothelial cytoskeleton through a pathway that is of an effector of Rac in endothelial cells B. Potempa S. Eichholtz T. Ridley A.J. J. 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PubMed Scopus Google Scholar), a signaling that were on of cells and in the of as a of it that by apo(a) of growth the of apo(a) is and in the of is with a of apo(a) on intracellular signaling We at this the that apo(a) Rho the of an of the apo(a) component of Lp(a) on endothelial cell intracellular signaling a for the atherogenic effects of It be that Lp(a), through its effects on intracellular signaling a in the endothelium that not the cytoskeletal rearrangements but also the increases in and cell adhesion molecule expression and of The of these effects of Lp(a) be a of used for were by Hall for Cell and Cell and of the was by the
Pellegrino et al. (Sun,) studied this question.