Transforming growth factor-beta is activated by plasmin and inhibits smooth muscle cell death in human saphenous vein.
BACKGROUND
The effect of activation of endogenous transforming growth factor-beta (TGF-beta) on smooth muscle cell apoptosis was assessed in human saphenous vein.


METHODS
Segments of human saphenous vein, obtained at the time of bypass graft surgery, were cultured for 14 days. During this time, smooth muscle cells accumulated in the intima as a result of proliferation and migration, partly counterbalanced by apoptotic cell death.


RESULTS
Addition of exogenous TGF-beta(1) had no effect on smooth muscle cell proliferation or apoptosis. However, antibody neutralization of endogenous TGF-beta(1) caused significant increases in smooth muscle cell death in the media and intima without any change in proliferation. A plasmin inhibitor (alpha-N-acetyl-L-lysine methyl ester), a specific urokinase-type plasminogen activator (uPA) inhibitor (amiloride) and an anti-catalytic anti-uPA antibody all caused decreases in the tissue content of active TGF-beta and increases in smooth muscle cell death in the media and intima.


CONCLUSIONS
These data suggest that the amount of TGF-beta in human saphenous vein is sufficient, when in the active form, to protect smooth muscle cells against apoptosis. Adding exogenous TGF-beta(1) has no beneficial effect, but decreasing the amount of active TGF-beta causes smooth muscle cells to undergo apoptosis. Plasmin, generated by uPA, appears to be an important activator of endogenous latent TGF-beta.
George
Sarah J
SJ
Bristol Heart Institute, University of Bristol, Bristol, UK.
Johnson
Jason L
JL
Smith
Melanie A
MA
Angelini
Gianni D
GD
Jackson
Christopher L
CL
D000584:Amiloride / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009924:Organ Culture Techniques; D012501:Saphenous Vein / Q000166:cytology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000276:immunology
D000906:Antibodies; D016212:Transforming Growth Factor beta; C069694:alpha-acetyllysine methyl ester; D000584:Amiloride; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D008239:Lysine