Antiangiogenic Activity of rPAI-123 Promotes Vasa Vasorum Regression in Hypercholesterolemic Mice Through a Plasmin-Dependent Mechanism

RATIONALE:The antiangiogenic activity of rPAI-123, a truncated plasminogen activator inhibitor-1 (PAI-1) protein, induces vasa vasorum collapse and significantly reduces plaque area and plaque cholesterol in hypercholesterolemic low-density lipoprotein receptor–deficient/apolipoprotein B48–deficient...

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Veröffentlicht in:Circulation research 2011-06, Vol.108 (12), p.1419-1428
Hauptverfasser: Mollmark, Jessica, Ravi, Saranya, Sun, Baiming, Shipman, Samantha, Buitendijk, Maarten, Simons, Michael, Mulligan-Kehoe, Mary Jo
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Sprache:eng
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Zusammenfassung:RATIONALE:The antiangiogenic activity of rPAI-123, a truncated plasminogen activator inhibitor-1 (PAI-1) protein, induces vasa vasorum collapse and significantly reduces plaque area and plaque cholesterol in hypercholesterolemic low-density lipoprotein receptor–deficient/apolipoprotein B48–deficient mice. OBJECTIVE:The objective of this study was to examine rPAI-123–stimulated mechanisms that cause vasa vasorum collapse. METHODS AND RESULTS:The rPAI-123 protein opposed PAI-1 antiproteolytic function by stimulating a 1.6-fold increase in plasmin activity compared with the saline-treated counterpart. The increased proteolytic activity corresponded to increased activity of matrix metalloproteinase-3 and degradation of fibrin(ogen), nidogen, and perlecan in the adventitia of descending aortas. PAI-1 activity was reduced by 48% in response to rPAI-123; however, PAI-1 protein expression levels were similar in the rPAI-123– and saline-treated hypercholesterolemic mice. Coimmunoprecipitation assays demonstrated a novel PAI-1–plasminogen complex in protein from the descending aorta of rPAI-123– and saline-treated mice, but complexed PAI-1 was 1.6-fold greater in rPAI-123–treated mice. Biochemical analyses demonstrated that rPAI-123 and PAI-1 binding interactions with plasminogen increased plasmin activity and reduced PAI-1 antiproteolytic activity. CONCLUSIONS:We conclude that rPAI-123 causes regression or collapse of adventitial vasa vasorum in hypercholesterolemic mice by stimulating an increase in plasmin activity. The rPAI-123–enhanced plasmin activity was achieved through a novel mechanism by which rPAI-123 and PAI-1 bound plasminogen in a cooperative manner to increase plasmin activity and reduce PAI-1 activity.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.111.246249