Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)[S]

Apo(a), the distinguishing protein component of lipoprotein(a) [Lp(a)], exhibits sequence similarity to plasminogen and can inhibit binding of plasminogen to cell surfaces. Plasmin generated on the surface of vascular cells plays a role in cell migration and proliferation, two of the fibroproliferat...

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Main Authors: Rocco Romagnuolo, Santica M. Marcovina, Michael B. Boffa, Marlys L. Koschinsky
Format: Article
Language:English
Published: Elsevier 2014-04-01
Series:Journal of Lipid Research
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S0022227520376525
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spelling doaj-30f060216671413c993dcbdb241ac1442021-04-28T06:02:18ZengElsevierJournal of Lipid Research0022-22752014-04-01554625634Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)[S]Rocco Romagnuolo0Santica M. Marcovina1Michael B. Boffa2Marlys L. Koschinsky3Department of Chemistry & Biochemistry, University of Windsor, Windsor, ON, Canada; andDepartment of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WADepartment of Chemistry & Biochemistry, University of Windsor, Windsor, ON, Canada; andTo whom correspondence should be addressed; Department of Chemistry & Biochemistry, University of Windsor, Windsor, ON, Canada; and; To whom correspondence should be addressedApo(a), the distinguishing protein component of lipoprotein(a) [Lp(a)], exhibits sequence similarity to plasminogen and can inhibit binding of plasminogen to cell surfaces. Plasmin generated on the surface of vascular cells plays a role in cell migration and proliferation, two of the fibroproliferative inflammatory events that underlie atherosclerosis. The ability of apo(a) to inhibit pericellular plasminogen activation on vascular cells was therefore evaluated. Two isoforms of apo(a), 12K and 17K, were found to significantly decrease tissue-type plasminogen activator-mediated plasminogen activation on human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes and macrophages. Lp(a) purified from human plasma decreased plasminogen activation on THP-1 monocytes and HUVECs but not on THP-1 macrophages. Removal of kringle V or the strong lysine binding site in kringle IV10 completely abolished the inhibitory effect of apo(a). Treatment with carboxypeptidase B to assess the roles of carboxyl-terminal lysines in cellular receptors leads in most cases to decreases in plasminogen activation as well as plasminogen and apo(a) binding; however, inhibition of plasminogen activation by apo(a) was unaffected. Our findings directly demonstrate that apo(a) inhibits pericellular plasminogen activation in all three cell types, although binding of apo(a) to cell-surface receptors containing carboxyl-terminal lysines does not appear to play a major role in the inhibition mechanism.http://www.sciencedirect.com/science/article/pii/S0022227520376525lipoprotein(a)atherosclerosisfibrinolysistissue-type plasminogen activatorcarboxypeptidase Bthrombin-activatable fibrinolysis inhibitor
collection DOAJ
language English
format Article
sources DOAJ
author Rocco Romagnuolo
Santica M. Marcovina
Michael B. Boffa
Marlys L. Koschinsky
spellingShingle Rocco Romagnuolo
Santica M. Marcovina
Michael B. Boffa
Marlys L. Koschinsky
Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)[S]
Journal of Lipid Research
lipoprotein(a)
atherosclerosis
fibrinolysis
tissue-type plasminogen activator
carboxypeptidase B
thrombin-activatable fibrinolysis inhibitor
author_facet Rocco Romagnuolo
Santica M. Marcovina
Michael B. Boffa
Marlys L. Koschinsky
author_sort Rocco Romagnuolo
title Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)[S]
title_short Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)[S]
title_full Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)[S]
title_fullStr Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)[S]
title_full_unstemmed Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)[S]
title_sort inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)[s]
publisher Elsevier
series Journal of Lipid Research
issn 0022-2275
publishDate 2014-04-01
description Apo(a), the distinguishing protein component of lipoprotein(a) [Lp(a)], exhibits sequence similarity to plasminogen and can inhibit binding of plasminogen to cell surfaces. Plasmin generated on the surface of vascular cells plays a role in cell migration and proliferation, two of the fibroproliferative inflammatory events that underlie atherosclerosis. The ability of apo(a) to inhibit pericellular plasminogen activation on vascular cells was therefore evaluated. Two isoforms of apo(a), 12K and 17K, were found to significantly decrease tissue-type plasminogen activator-mediated plasminogen activation on human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes and macrophages. Lp(a) purified from human plasma decreased plasminogen activation on THP-1 monocytes and HUVECs but not on THP-1 macrophages. Removal of kringle V or the strong lysine binding site in kringle IV10 completely abolished the inhibitory effect of apo(a). Treatment with carboxypeptidase B to assess the roles of carboxyl-terminal lysines in cellular receptors leads in most cases to decreases in plasminogen activation as well as plasminogen and apo(a) binding; however, inhibition of plasminogen activation by apo(a) was unaffected. Our findings directly demonstrate that apo(a) inhibits pericellular plasminogen activation in all three cell types, although binding of apo(a) to cell-surface receptors containing carboxyl-terminal lysines does not appear to play a major role in the inhibition mechanism.
topic lipoprotein(a)
atherosclerosis
fibrinolysis
tissue-type plasminogen activator
carboxypeptidase B
thrombin-activatable fibrinolysis inhibitor
url http://www.sciencedirect.com/science/article/pii/S0022227520376525
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