Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator.
Although thrombolysis with tissue plasminogen activator (tPA) is a stroke therapy approved by the US Food and Drug Administration, its efficacy may be limited by neurotoxic side effects. Recently, proteolytic damage involving matrix metalloproteinases (MMPs) have been implicated. In experimental embolic stroke models, MMP inhibitors decreased cerebral hemorrhage and injury after treatment with tPA. MMPs comprise a family of zinc endopeptidases that can modify several components of the extracellular matrix. In particular, the gelatinases MMP-2 and MMP-9 can degrade neurovascular matrix integrity. MMP-9 promotes neuronal death by disrupting cell-matrix interactions, and MMP-9 knockout mice have reduced blood-brain barrier leakage and infarction after cerebral ischemia. Hence it is possible that tPA upregulates MMPs in the brain, and that subsequent matrix degradation causes brain injury. Here we show that tPA upregulates MMP-9 in cell culture and in vivo. MMP-9 levels were lower in tPA knockouts compared with wild-type mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP-9 was upregulated when recombinant tPA was added. RNA interference (RNAi) suggested that this response was mediated by the low-density lipoprotein receptor-related protein (LRP), which avidly binds tPA and possesses signaling properties. Targeting the tPA-LRP signaling pathway in brain may offer new approaches for decreasing neurotoxicity and improving stroke therapy.
Wang
Xiaoying
X
Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Charlestown, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA. wangxi@helix.mgh.harvard.edu
Lee
Sun-Ryung
SR
Arai
Ken
K
Lee
Seong-Ryong
SR
Tsuji
Kiyoshi
K
Rebeck
G William
GW
Lo
Eng H
EH
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004790:Enzyme Induction; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use
D018110:Receptors, Lipoprotein; D010959:Tissue Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9