Apolipoprotein(a) inhibits the conversion of Glu‐plasminogen to Lys‐plasminogen: a novel mechanism for lipoprotein(a)‐mediated inhibition of plasminogen activation
Abstract:To cite this article: Feric NT, Boffa MB, Johnston SM, Koschinsky ML. Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for lipoprotein(a)-mediated inhibition of plasminogen activation. J Thromb Haemost 2008; 6: 2113-20.Summary. Background: Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with an increased risk for thrombotic disorders. Lp(a) is a unique lipoprotein consisting of a low-density lipoprotein-like moiety covalently linked to a… Show more
“…Interestingly, however, the effect of apo(a) isoform size on affinity for fibrin was only seen in the context of Lp(a) particles, as there was no difference in fibrin affinity seen in a panel of recombinant apo(a) species varying in KIV 2 repeat number, but not complexed to apoB-100 (54). These findings are in agreement with other functional studies in which isoform size did not affect the ability of apo(a) alone to inhibit plasminmediated conversion of Glu-plasminogen to Lys-plasminogen (49). Likewise, binding of Lp(a) to mononuclear cells (THP-1 cell line) was influenced by apo(a) isoform size, with a smaller isoform displaying a higher affinity and a greater ability to inhibit plasminogen binding (64).…”
Section: Downloaded Fromsupporting
confidence: 82%
“…In particular, our own laboratory has amassed a large collection of recombinant apo(a) variants that allows us to systematically screen the various domains in apo(a) for functional roles. Through these studies, we have found that several domains are required for maximally-efficient inhibition of tPA-mediated plasminogen activation or of plasminmediated Glu-to Lys-plasminogen conversion (47,49). The strong LBSs in KIV 10 , as well as the KV, are required for both inhibitory activities, and additional sequences within KIV 5 -KIV 8 are also required to inhibit plasminogen activation.…”
Section: Structural Determinants On Apo(a) For Anti-fibrinolytic Effectsmentioning
confidence: 99%
“…Activation of plasminogen by tissuetype plasminogen activator (tPA) does not occur at a meaningful rate in the absence of a fibrin surface, whereas lysine-dependent interactions between plasminogen and feedback step of plasmin-mediated Glu-to Lys-plasminogen conversion in the context of fibrin (Fig. 3) (49). This last result is noteworthy in that it had been previously found that apo(a) was unable to inhibit fibrinolysis in a system of purified components in which the Glu-to Lys-plasminogen step was bypassed by the addition of only Lys-plasminogen (46).…”
Section: Interference With Functions Of Plasminogenmentioning
“…Interestingly, however, the effect of apo(a) isoform size on affinity for fibrin was only seen in the context of Lp(a) particles, as there was no difference in fibrin affinity seen in a panel of recombinant apo(a) species varying in KIV 2 repeat number, but not complexed to apoB-100 (54). These findings are in agreement with other functional studies in which isoform size did not affect the ability of apo(a) alone to inhibit plasminmediated conversion of Glu-plasminogen to Lys-plasminogen (49). Likewise, binding of Lp(a) to mononuclear cells (THP-1 cell line) was influenced by apo(a) isoform size, with a smaller isoform displaying a higher affinity and a greater ability to inhibit plasminogen binding (64).…”
Section: Downloaded Fromsupporting
confidence: 82%
“…In particular, our own laboratory has amassed a large collection of recombinant apo(a) variants that allows us to systematically screen the various domains in apo(a) for functional roles. Through these studies, we have found that several domains are required for maximally-efficient inhibition of tPA-mediated plasminogen activation or of plasminmediated Glu-to Lys-plasminogen conversion (47,49). The strong LBSs in KIV 10 , as well as the KV, are required for both inhibitory activities, and additional sequences within KIV 5 -KIV 8 are also required to inhibit plasminogen activation.…”
Section: Structural Determinants On Apo(a) For Anti-fibrinolytic Effectsmentioning
confidence: 99%
“…Activation of plasminogen by tissuetype plasminogen activator (tPA) does not occur at a meaningful rate in the absence of a fibrin surface, whereas lysine-dependent interactions between plasminogen and feedback step of plasmin-mediated Glu-to Lys-plasminogen conversion in the context of fibrin (Fig. 3) (49). This last result is noteworthy in that it had been previously found that apo(a) was unable to inhibit fibrinolysis in a system of purified components in which the Glu-to Lys-plasminogen step was bypassed by the addition of only Lys-plasminogen (46).…”
Section: Interference With Functions Of Plasminogenmentioning
“…Figure 2B displays the r-apo(a) variants representing naturallyoccurring isoforms as well as various deletion and point mutants. These r-apo(a) constructs, which were derived from the original published human cDNA of apo(a), were generated from the expression plasmid pRK5 ha17 and their construction, expression, and purifi cation have been previously described (27)(28)(29)(30) ) were mutated to alanine with similar techniques as for the above r-apo(a) constructs. A construct comprised of the 8K-IV wild-type (WT) and 8K-IV lysine-binding defective mutant (LBS ؊ ) r-apo(a), used to generate transgenic mice with a truncated apo(a) as previously described (31)(32)(33), was also studied and their construction is described below.…”
Section: Tandem Lc-ms/ms Analysis Of Oxpls On R-apo(a) Constructsmentioning
“…A novel contribution to the understanding of Lp(a)/apo-a-mediated inhibition of plasminogen activation comes from results showing the ability of the apo(a) component of Lp(a) to inhibit the key positive feedback step of plasmin-mediated conversion of Gluplasminogen to Lys-plasminogen an essential step for fibrin clot lysis [78]. Interestingly, with the exception of the smallest naturally-occurring isoform of apo(a), isoform size was found not to contribute to the inhibitory capacity of apo(a).…”
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