Tissue type plasminogen activator facilitates NMDA-receptor-mediated retinal apoptosis through an independent fibrinolytic cascade.
OBJECTIVE
To investigate the association between apoptosis and the fibrinolytic system in retinal cell damage.


METHODS
Tissue type plasminogen activator-deficient (tPA(-/-)), urokinase type plasminogen activator-deficient (uPA(-/-)), plasminogen activator inhibitor-1-deficient (PAI-1(-/-)), alpha2 antiplasmin-deficient (alpha2 AP(-/-)) mice, and their wild-type counterparts were used. Retinal cell damage was induced by intravitreal injection of the excitotoxin N-methyl-d-aspartate (NMDA). The TdT-dUTP terminal nick-end labeling (TUNEL) method was used to examine retinal cell damage.


RESULTS
tPA(-/-) mice were resistant to retinal cell damage caused by administration of NMDA, and PAI-1(-/-) mice were more injured than their wild-type. No significant difference was observed between uPA(-/-) or alpha2 AP(-/-) and their wild-type mice.


CONCLUSIONS
The results strongly suggest that endogenous tPA, but not uPA acts as a facilitator in NMDA-induced retinal cell damage, and that its mechanism may not be associated with cleavage of plasminogen into plasmin in the fibrinolytic cascade.
Kumada
Masako
M
Departments of Pharmacology, Gifu Graduate University School of Medicine, Gifu, Japan.
Niwa
Masayuki
M
Hara
Akira
A
Matsuno
Hiroyuki
H
Mori
Hideki
H
Ueshima
Shigeru
S
Matsuo
Osamu
O
Yamamoto
Tetsuya
T
Kozawa
Osamu
O
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005136:Eye Proteins / Q000502:physiology; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D020287:In Situ Nick-End Labeling; D007267:Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000633:toxicity*; D009414:Nerve Growth Factors / Q000502:physiology; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology; D010960:Plasminogen Activators / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015843:Serpins / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology; D000099174:Pigment Epithelium-Derived Factor
D018690:Excitatory Amino Acid Agonists; D005136:Eye Proteins; D005341:Fibrinolysin; D016202:N-Methylaspartate; D009414:Nerve Growth Factors; D010958:Plasminogen; D017395:Plasminogen Activator Inhibitor 1; D010960:Plasminogen Activators; D016194:Receptors, N-Methyl-D-Aspartate; D015843:Serpins; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D000099174:Pigment Epithelium-Derived Factor