Midkine enhances fibrinolytic activity of bovine endothelial cells.
A hitherto unknown function of midkine (MK) was found in the regulation of fibrinolytic activity of vascular endothelial cells. Recombinant murine MK enhanced plasminogen activator (PA)/plasmin levels in bovine aortic endothelial cells (BAECs) in a dose- and time-dependent manner. After incubation with 10 ng/ml MK for 18 h, PA and plasmin levels increased 6- and 4-fold, respectively. This effect was attributed to a moderate upregulation of urokinase-type PA expression as well as to a significant down-regulation of PA inhibitor-1 (PAI-1) expression. BAECs constitutively synthesized and secreted MK and its production was enhanced 2-fold with 1 microM retinoic acid or 10 microM retinol. It was found that MK served as a substrate for tissue transglutaminase. In the culture medium, MK existed as a transglutaminase-mediated complex of 36 kDa. Addition of anti-MK antibody to BAEC cultures resulted in a decrease of basal PA activity and an increase of basal PAI-1 levels and attenuated the ability of retinol to enhance PA activity 50% and potentiated the ability to increase PAI-1 levels 4-fold. Furthermore, MK and basic fibroblast growth factor (bFGF) acted more than additively in enhancing PA levels. We conclude that in BAECs MK is a novel autocrine factor sustaining the fibrinolytic property. MK functions as a mediator of retinoid and cooperates with bFGF to enhance fibrinolytic activity of BAECs.
Kojima
S
S
Laboratory of Gene Technology and Safety, Tsukuba Life Science Center, Institute of Physical and Chemical Research (RIKEN), Ibaraki, Japan.
Muramatsu
H
H
Amanuma
H
H
Muramatsu
T
T
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D016207:Cytokines; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005341:Fibrinolysin / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D000078792:Midkine; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D010960:Plasminogen Activators / Q000032:analysis; D014801:Vitamin A / Q000494:pharmacology
D002352:Carrier Proteins; D016207:Cytokines; D017395:Plasminogen Activator Inhibitor 1; D016222:Fibroblast Growth Factor 2; D014801:Vitamin A; D000078792:Midkine; D010960:Plasminogen Activators; D005341:Fibrinolysin