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Lipoprotein receptor–mediated induction of matrix metalloproteinase by tissue plasminogen activator

Abstract

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 effects1,2. 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 tPA3,4. MMPs comprise a family of zinc endopeptidases that can modify several components of the extracellular matrix5,6. In particular, the gelatinases MMP-2 and MMP-9 can degrade neurovascular matrix integrity. MMP-9 promotes neuronal death by disrupting cell-matrix interactions7, and MMP-9 knockout mice have reduced blood-brain barrier leakage and infarction after cerebral ischemia8. 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 tPA9 and possesses signaling properties10. Targeting the tPA-LRP signaling pathway in brain may offer new approaches for decreasing neurotoxicity and improving stroke therapy.

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Figure 1: MMP-9 upregulation after focal cerebral ischemia in mouse brain.
Figure 2: Analyses of tPA-induced production of MMPs in human cerebral microvascular endothelial cells.
Figure 3: Effects of LRP RNAi on tPA-induced MMP-9 response.
Figure 4: Lack of tPA-induced MMP-9 upregulation in LRP-deficient MEF cells at 24 h.

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Acknowledgements

This work was supported in part by National Institute of Neurological Disorders and Stroke grants R01-NS37074, R01-NS38731, R01-NS40529, R01-AG14473 and P50-NS10828. We thank R. Zhu and J. Bai for assistance with RNAi experiments, and J.-C. Jung for helpful discussions on mRNA measurement.

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Correspondence to Xiaoying Wang or Eng H Lo.

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Wang, X., Lee, SR., Arai, K. et al. Lipoprotein receptor–mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 9, 1313–1317 (2003). https://doi.org/10.1038/nm926

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