Tissue inhibitor of metalloproteinases protect blood-brain barrier disruption in focal cerebral ischemia.
Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood-brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1(-/-) and TIMP-2(-/-) mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1(-/-) mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.
Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Motoaki
M
Fujimoto
Yasushi
Y
Takagi
Tomohiro
T
Aoki
Makoto
M
Hayase
Takeshi
T
Marumo
Masanori
M
Gomi
Masaki
M
Nishimura
Hiroharu
H
Kataoka
Nobuo
N
Hashimoto
Kazuhiko
K
Nozaki
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9